here - National Medicinal Chemistry Symposium

 The 35th National Medicinal Chemistry Symposium June 26‐29, 2016 Chicago, IL www.nmcs.com Welcome to Chicago! We are pleased to bring you the 35th National Medicinal Chemistry Symposium (NMCS). The series began in 1948 and continues to be a premier conference for the Medicinal Chemistry Division (MEDI) of the American Chemical Society. Our goal has been to provide a venue for symposia topics at the cutting edge of medicinal chemistry and those disciplines with which it interfaces. The meeting is intended to be an intimate four days of stimulating lectures and intellectual engagement. We are indebted to the MEDI Executive Committee, and to the NMCS scientific and organizing committees who have worked diligently over the past year to provide you with an excellent line‐up of speakers. We also are pleased to introduce Dr. Michael Sofia, the 2016 IUPAC Richter Prize Award Winner, and this year’s ACS Division of Medicinal Chemistry Award recipient Dr. Manoj Desai. We plan to honor both Mike and Manoj in their storied accomplishments in our program on opening night. You will find a select group of exhibitors joining us this year. We hope you will take the time to meet them, and in the process, get the chance to win some first‐rate prizes donated by our hosts here at the iconic Palmer House, the Hilton Chicago, and The Drake Hotel. We also thank our sponsors for their generous financial contributions to this conference. Above all, we thank you for your attendance at this conference and encourage your active participation throughout these four days. It is our goal to continue the tradition of NMCS excellence, and we welcome any input or suggestions you may have on the Symposium. Watch www.nmcs.info for information on the 36th NMCS, to be held in 2018! Have a great time here in Chicago, Sincerely yours, D. Eric Walters Rosalind Franklin University Michael Kort AbbVie Inc. 2 The 2016 National Medicinal Chemistry Symposium is made possible in part by the generous support of the following organizations: 3 NMCS 2016 is pleased to welcome the following exhibitors: 4 Experience the sights and sounds of Chicago! Tuesday afternoon you have the opportunity to take in the sights and sounds of Chicago. There are a number of world class activities within walking distance of the Palmer House Hotel. The prices below reflect the walk in ticket price. 
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Museum campus (Shedd Aquarium, Adler Planetarium, Field Museum) Navy Pier – a free family friendly attraction with a Ferris wheel and lots of great food! Michigan Ave @ Upper Wacker – Boat tours will leave from this stop – look to the river bank for signs & to purchase tickets. Art Institute – a quick walk and a great gift shop! Millennium and Grant Parks – Be sure to check out Buckingham fountain and the lake! Chicago has so much to offer. Stop by the hotel concierge for additional information and suggestions. Here are a couple of helpful websites. Take advantage of new acquaintances you will make at the NMCS to explore the city together. http://www.events12.com/chicago/june/ http://www.choosechicago.com/things‐to‐do/chicago‐events/events‐calendar/ If sporting events peak your interest, the Chicago White Sox will be in town during the conference. http://chicago.whitesox.mlb.com. The Chicago Cubs will be on the road. 5 Walking tours from the Chicago Architecture Foundation $20 Duration 90 minutes Recommended tour: Must‐See Chicago “Must‐See Chicago” is a fast‐paced, 90‐minute tour introducing Chicago and many of its most famous buildings, including the Art Institute of Chicago, Sears (Willis) Tower, Wrigley Building, Chicago Theatre and John Hancock Center. As you explore downtown, you’ll hop on and off the city’s signature “L” trains (stairs are required). The tour begins at the Chicago Architecture Foundation and wraps up at the intersection of Michigan and Chicago Avenues, the heart of the Magnificent Mile” Additional tours are available from the Foundation at their headquarters (224 S Michigan Ave, Chicago, IL 60604). Don’t miss the gift shop or the Lego model of Chicago! 6 Chicago Architecture Foundation River cruise $42 Duration 1.5 h Experience the “top tour in Chicago and one of the top ten tours in the U.S.” according to TripAdvisor users. The Chicago Architecture Foundation River Cruise is a must for out‐of‐
towners and Chicagoans alike. CAF‐certified volunteer tour guides—called docents—interpret more than 50 buildings along the Chicago River. You’ll find out how Chicago grew from a small settlement into one of the world’s largest cities in less than 100 years. In 90 minutes, get the real story on Chicago architecture and its history. 7 Art Institute of Chicago Adults $25, Students $19 (make sure to bring your ID) A must‐see for local, national, and international groups of all ages. From our world‐renowned French Impressionist collection to American art favorites like Grant Wood's American Gothic and ancient treasures from across the globe to modern masterpieces by Dalí, Matisse, and Picasso. The museum has something for everyone—art experts and new museum‐goers alike. 8 Museum Campus Shedd Aquarium $8 adult Field Museum $22 adult, $19 student Adler Planetarium $25 adult Chicago's Museum Campus was created after a reconfiguration of Lake Shore Drive in 1998. Previously, lanes ran through the middle of the area, dividing it up and creating some tricky navigation from the parking lots to the museums. The lanes have been moved to the west, and the major attractions of the Museum Campus (the Shedd Aquarium, Field Museum, Adler Planetarium, and Soldier Field) are all tied together by green space. 9 Navy Pier Navy Pier has enjoyed a remarkable evolution. Originally designed for shipping and recreational purposes, the facility has evolved into a premiere entertainment center while also offering exposition facilities. There are many great souvenir shops, food options, and vistas from the pier. Navy Pier is free to explore with many options for entertainment and delicious fare! Once you are here, if you would like to explore the River North neighborhood, check out the free trolley! Map: https://1t9gqf1rdexwil9k1rrz1j111‐wpengine.netdna‐ssl.com/wp‐
content/uploads/2014/10/trolley‐route‐map.pdf https://navypier.com 10 Sunday June 26 Registration Open (9:00 am ‐ 9:00 pm) Welcome and Introduction (Empire Room) 1:00 pm ‐ 1:30 pm Welcome to the 2016 National Medicinal Chemistry Conference D. Eric Walters (Rosalind Franklin University of Medicine and Science) Michael Kort (AbbVie) Pharmacokinetic Concepts and Controversies in Modern Drug Design Organizers and Session Chairs: Li Di (Pfizer) and Scott Monk (Eli Lilly) 1:30 pm ‐ 2:10 pm Xinrong Liu (Genentech) “Misconceptions in Plasma Protein Binding” 2:10 pm ‐ 2:50 pm Kevin Beaumont (Pfizer) “Volume of Distribution in Drug Design” 2:50 pm ‐ 3:10 pm Break 3:10 pm ‐ 3:50 pm Prashant Desai (Eli Lilly) “Realistic Application of In Silico ADME Tools Impacting Drug Discovery” 3:50 pm ‐ 4:30 pm Matt Hutzler (Q2 Solutions) ”Don't Get Burned by Aldehyde Oxidase” 4:30 pm ‐ 4:50 pm Roundtable Discussion (all session speakers) Welcome Reception (Honoré Room) 5:00 pm ‐ 6:30 pm Welcome Reception ACS Division of Medicinal Chemistry Award and IUPAC Richter Prize Symposium (Empire Room) Organizers: Michael Kort (AbbVie) and D. Eric Walters (Rosalind Franklin University of Medicine and Science); Session Chair: Thomas Bannister (Scripps Florida) 6:30 pm ‐ 7:30 pm 2016 IUPAC Richter Prize Award Winner, Michael Sofia (Arbutus Biopharma) “The Discovery of Sofosbuvir: A Breakthrough Curative Therapy for Hepatitis C” 7:30 pm ‐ 8:30 pm 2016 Division of Medicinal Chemistry Award Winner, Manoj C. Desai (Gilead) “Discovery of Cobicistat and Eleclazine” 11 Monday June 27 Breakfast (Mezzanine level) 7:00 am ‐ 8:30 am Continental Breakfast Available Transcription Factors as Drug Targets (Empire Room) Organizer: Terry Moore (University of Illinois‐Chicago); Session Chair: Anna Mapp (University of Michigan) Sponsored by Kalexsyn 8:30 am ‐ 9:10 am Paramjit Arora (New York University) “Targeting Transcriptional Coactivators with Rationally Designed Protein Domain Mimetics” 9:10 am ‐ 9:50 am Jolanta Grembecka (University of Michigan) “Structure‐Based Development of Menin‐MLL Inhibitors for Disruption of Transcriptional Regulation in Cancer” 9:50 am ‐ 10:10 am Break 10:10 am ‐ 10:50 am Jeffrey Kerns (GlaxoSmithKline) “Small Molecule Activators of Nrf2 and the Antioxidant Response” 10:50 am ‐ 11:30 am Anna Mapp (University of Michigan) “Allosteric Modulators of Transcriptional Activator‐Coactivator Complexes” Lunch (Red Lacquer Room, 4th Floor) 11:45 am ‐ 1:15 pm Lunch Epigenetic Mechanisms of Action in the Treatment of Human Diseases (Empire Room) Organizer and Session Chair: Jean‐Christophe Harmange (Third Rock Ventures) 1:30 pm ‐ 2:10 pm Rima Al Awar (Ontario Institute for Cancer Research) “OICR‐9429: A Small Molecule Antagonist of the WDR5‐MLL Interaction” 2:10 pm ‐ 2:50 pm Christoph Gaul (Novartis) “The Discovery of DOT1L Inhibitors by Fragment‐Based Approaches” 2:50 pm ‐ 3:10 pm Break 3:10 pm ‐ 3:50 pm Victor Gehling (Constellation Pharmaceuticals) “Discovery of Selective, Cell‐
Permeable KDM5 Inhibitors” 3:50 pm ‐ 4:30 pm Keith McDaniel (AbbVie) “The Discovery of BET Bromodomain Inhibitor ABBV‐
075” 12 Dinner (Empire Room) 5:30 pm ‐ 6:30 pm Buffet Dinner Poster Session (Exhibit Hall) Presiding: Kristine Frank (AbbVie) and Matthew Hill (Bristol‐Myers Squibb) Sponsored by Enamine 6:30 pm ‐ 9:00 pm Poster Session Tuesday June 28 Breakfast (Mezzanine level) 7:00 am ‐ 8:30 am Continental Breakfast Available Challenges and Recent Advances in the Treatment of Neurodegenerative Disorders (Empire Room) Organizer: Junliang Hao (Eli Lilly); Session Chair: Warren Porter (Eli Lilly) 8:30 am ‐ 9:10 am Olivier Corminboeuf (Actelion Pharmaceuticals) “Tackling Inflammation with a Pro‐Resolution FPR2 Agonist” 9:10 am ‐ 9:50 am Robert Mach (University of Pennsylvania) “Progress in the Development of a PET Radiotracer for Imaging Alpha Synuclein” 9:50 am ‐ 10:10 am Break 10:10 am ‐ 10:50 am Daniel Oehlrich (Janssen Pharmaceuticals) “The Evolution of In Vivo Efficacious BACE1 Inhibitors” 10:50 am ‐ 11:30 am David Vocadlo (Simon Fraser University) “OGA Inhibitors as a Potential Disease Modifying Approach for Alzheimer Disease: Structure‐Activity Relationships of OGA Inhibitors” 11:45 a.m Boxed lunch to go and free time for Chicago area activities Wednesday June 29 Breakfast (Mezzanine level) 7:00 am ‐ 8:30 am Continental Breakfast Available Innovation through Collaboration (Empire Room) Organizer: Julia Clay (Eli Lilly); Session Chair: Maria Alvim‐Gaston (Eli Lilly) 8:30 am ‐ 9:10 am Paul Willis (Medicines for Malaria Venture) “The Discovery of Novel Small Molecule Antimalarials through a Global Network of Partnerships” 13 9:10 am ‐ 9:50 am 9:50 am ‐ 10:10 am 10:10 am ‐ 10:50 am 10:50 am ‐ 11:30 am Craig Lindsley (Vanderbilt University) ”Leveraging Foundation, Corporate and NIH Support for Academic Drug Discovery” Break Maria Alvim‐Gaston (Eli Lilly) “Open Innovation Drug Discovery Program: For Scientists by Scientists. Making Lives Better Together” Jimmy Wu (Dartmouth College) “Integrating OIDD into an Academic Research Program: Identification of Novel GLP‐1 Secretagogues and their Biological Target” Lunch & Learn (Monroe Ballroom) – This is an advanced registration event. Hosted by Lathrop & Gage 11:45 am ‐ 1:15 pm Elizabeth Karnas (Lathrop & Gage) “Pharmaceutical Patent Prosecution Primer and Small Molecule Obviousness” Lunch (Mezzanine level) 11:45 am ‐ 1:15 pm Lunch Drugging the Undruggable (Empire Room) Organizer and Session Chair: Keith McDaniel (AbbVie) 1:30 pm ‐ 2:10 pm Michelle Arkin (University of California, San Francisco) “Inhibitors of Protein‐
Protein Interactions: Reflections and Projections” 2:10 pm ‐ 2:50 pm Craig Crews (Yale University) “PROTACS: Induced Protein Degradation as a Therapeutic Strategy” 2:50 pm ‐ 3:10 pm Break 3:10 pm ‐ 3:50 pm Jinglan Zhou (Vertex Pharmaceuticals) “Discovery of Ivacaftor, a CFTR Potentiator for the Treatment of Cystic Fibrosis” 3:50 pm ‐ 4:30 pm Kaustav Biswas (Amgen) “Nav1.7 Inhibitory Peptides from Tarantula Venom: Engineering Potency and Selectivity Towards Developing Novel Pain Therapeutics” Conclusion and Departure 4:45 pm Departure 14 Oral Presentations 15 Misconceptions in Plasma Protein Binding Xingrong Liu Drug Metabolism and Pharmacokinetics, Genentech, Inc It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. Therefore, one of the objectives in drug design is to optimize the compound structure to increase in vivo unbound drug concentration. Theoretical analyses and experimental observations will be presented to illustrate that low plasma protein binding does not necessarily lead to high in vivo unbound plasma concentration. Similarly, low brain tissue binding does not lead to high in vivo unbound brain tissue concentration. Instead, low intrinsic clearance leads to high in vivo unbound plasma concentration, and low efflux transport activity at the blood−brain barrier leads to high unbound brain concentra on. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs, but these parameters should not be targeted for optimization in drug design. 16 Volume of Distribution in Drug Design Kevin Beaumont Pfizer Volume of distribution is the pharmacokinetic parameter that relates concentrations in blood/plasma to the amount of drug in the body at any given time after dosing. It is an important parameter because in combination with clearance, it drives half‐life and consequently dosing frequency. It is therefore an important consideration in drug design. For a given chemical series, volume of distribution is defined by physicochemistry. Acids tend to be highly bound to albumen in blood and therefore tend to exhibit volumes of distribution limited to where albumen can reach in the body (i.e., the extravascular space). Neutral molecules show a positive correlation between volume of distribution and log P, driven by binding to membranes in tissues. Bases will show higher volumes of distribution than neutrals by virtue of a combination of log P and charge driven binding with cell membranes. Consequently, adding a basic center and increasing Log P, without increasing metabolism is one potential method to increase volume of distribution. Other methods of increasing volume of distribution will also be discussed. 17 Realistic Application of In Silico ADME Tools Impacting Drug Discovery Prashant Desai Computational ADME, Eli Lilly and Company In today’s drug discovery paradigm, identification and resolution of ADME challenges is no longer confined to the lead optimization phase, but is now an integral part of all stages of drug discovery. To that end, integration of in silico in vitro and in vivo ADME models has been demonstrated to be a valuable strategy towards efficient delivery of high quality clinical candidates with optimal balance of properties. In this presentation, some of the myths surrounding in silico models will be addressed while emphasizing the importance of setting realistic expectations from use of such models in light of the inherent variability of the experimental data that inform these models. Several examples demonstrating the impact of in silico ADME models on the efficiency of drug discovery projects will be discussed. 18 Don’t Get Burned by Aldehyde Oxidase J. Matthew Hutzler Q2 Solutions, Bioanalytical and ADME Labs, Indianapolis, IN Aldehyde oxidase (AO) is a cytosolic molybdo‐flavoprotein that has emerged as a relevant drug‐
metabolizing enzyme involved in the biotransformation of heterocyclic‐containing drugs. Due to subcellular location and profound species differences in activity (human>>rat with no active AO in dog), conventional in vitro metabolism assays using human liver microsomes and pharmacokinetic studies in rat and dog have generally been unsuccessful in identifying a role for AO in the metabolism of drug molecules. These misses have resulted in costly failures for multiple clinical programs. This presentation will highlight select case study examples of clinical failures due to poor oral drug exposure and unexpected toxicology, as well as the many confounding factors associated with confirming a role for AO in the metabolism of a candidate drug. Topics covering the use of liver cytosol or cryopreserved hepatocytes, extrahepatic expression of AO, complications with extrapolation of in vitro data (IVIVE), and alternative scaling approaches using appropriate surrogate species for predicting clearance in human will be discussed. In addition, pharmacological targets that require specific pharmacophores that may be more susceptible to AO metabolism, and structural modifications that may modulate AO‐mediated metabolism will be highlighted. Overall, an integrated approach for identifying AO as relevant in the metabolism of a drug candidate, and contrasting views for the steps to take for either moving forward into the clinic with confidence, or eliminating the AO pathway altogether, will be presented. 19 Targeting transcriptional coactivators with rationally designed protein domain mimetics Paramjit Arora New York University Development of specific ligands for protein targets that help decode the complexities of protein‐protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high‐throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein‐protein interactions remains a challenge for synthetic chemists. Proteins often utilize small folded domains for recognition of other biomolecules. The basic hypothesis guiding our research is that by mimicking these domains we can modulate the function of a particular protein with metabolically stable synthetic molecules. This presentation will discuss computational and synthetic methods to develop protein domain mimics (PDMs) as modulators of protein‐protein interactions, specifically on the targeting of the p300 coactivator to reactivate p53 and Rb in head and neck squamous cell carcinoma. 20 Structure‐based development of menin‐MLL Jolanta Grembecka University of Michigan Menin is a protein that directly interacts with the Mixed Lineage Leukemia 1 (MLL1) histone methyltransferase, and this protein‐protein interaction (PPI) is required for recruitment of the MLL1 complex to the target genes to regulate their expression. Menin also binds to MLL fusion proteins and this interaction is involved in acute leukemia with MLL translocations. Accumulating evidences suggest that the menin‐MLL1 mediated transcriptional regulation also plays an important role in solid tumors, including prostate cancer. Therefore, small molecule inhibition of the menin‐MLL interaction might represent a novel promising strategy for the treatment of various cancers. We developed small molecules that specifically bind to menin and inhibit the menin‐MLL interaction in vitro and in cells. Using a combination of structure‐based design and medicinal chemistry efforts we extensively optimized the thienopyrimidine class of menin‐MLL inhibitors to improve both their potency and drug‐like properties. This work resulted in low nanomolar inhibitors of the menin‐MLL interaction with optimized selectivity, solubility and favorable pharmacokinetic profile, representing the first in vivo active compounds targeting this protein‐
protein interaction. These compounds demonstrate strong effect and specific mechanism of action in MLL leukemia cells and block progression of acute leukemia in mice models of MLL leukemia. Besides, the menin‐MLL inhibitors we developed showed pronounced in vitro and in vivo efficacy in metastatic castration resistant prostate cancer models, further validating their therapeutic potential. Our work demonstrates how disruption of transcriptional regulation by small molecule inhibitors of the menin‐MLL interaction can lead to new potential therapeutic approaches in cancer. 21 Small molecule activators of Nrf2 and the antioxidant respons Jeffrey Kerns GlaxoSmithKline The Nrf2 (NF‐E2‐related factor 2) transcription factor plays a key role in cellular stress response mechanisms. As a result of both oxidative and alkylative stress, Nrf2 up‐regulates approximately 150 gene products aimed at detoxification including glutathione synthesis, reactive oxygen species (ROS) scavenging, and drug metabolism. As a cellular defense mechanism, defective regulation of Nrf2 is implicated in a number of disease processes. Nrf2 is dynamically regulated. Under basal conditions, Nrf2 is associated with the cysteine‐rich Keap1 (Kelch‐like ECH‐associated protein 1) protein. Keap1 is central in orchestrating the ubiquitination and subsequent degradation of Nrf2 through its association with the Cullin E3 ubiquitin ligase Cul3 keeping Nrf2 at very low concentrations under non‐stressed conditions. Nrf2 activation via covalent modification of cysteine‐rich Keap1 is well precedented across a variety of natural and naturally derived products. In this regard, we have optimized a series of sulforaphane and coumarin analogs that activate Nrf2 and the downstream antioxidant response via covalent modification of cysteine residues in Keap1. In addition, we have used a fragment based approach to develop a potent series of non‐covalent small‐molecule inhibitors of the Nrf2:Keap1 interaction. Like covalent activators, this series activates Nrf2 and provides protection from oxidative stress both in cells and in‐vivo. 22 Allosteric modulators of transcriptional activator‐coactivator complexes Anna Mapp University of Michigan Within the chemical space of protein‐protein interactions (PPIs), transient, modest affinity PPIs play a central role in a variety of cellular functions, including protein folding and transcription. Dysregulation of this class of PPIs is at the heart of diseases ranging from cancer to neurodegenerative disorders. For example, in several types of AML, leukemogenesis is dependent upon the loss of one transcriptional activator‐coactivator interaction (MLL‐p300) and the maintenance or amplification of a second (cMyb‐p300). Despite their importance and their prevalence, such transient and modest affinity PPIs are often classified as ‘undruggable’, with few successful strategies for small molecule modulator discovery. A significant challenge has been that the binding partners often have significant disorder and are thus difficult to characterize structurally alone or in complex. A strategy for the identification of chemical co‐
chaperones that capture particular conformations of transcriptional coactivators and in doing so selectively modulate the assembly of transcriptional activator‐coactivator complexes in vitro and in cells will be described. 23 OICR‐9429: A Small Molecule Antagonist of the WDR5‐MLL Interaction Matthäus Getlik,1 David Smil,2 Carlos Zepeda‐Velázquez,1 Yuri Bolshan,2 Gennadiy Poda,1 Guillermo Senisterra,2 Hong Wu,2 Abdellah Allali‐Hassani,2 Gregory A. Wasney 2 Dalia Barsyte‐Lovejoy,2 Ludmila Dombrovski,2 Aiping Dong 2 Hao He 2 Alma Seitova,2 Irene Chau,2 Fengling Li,2 Jean‐François Couture,2 Ekaterina Kuznetsova,2 Richard Marcellus,1Taraneh Hajian,2 Taira Kiyota,1 Kong T. Nguyen,2 Matthieu Schapira,2 Peter J. Brown,2 Cheryl H. Arrowsmith,2 Masoud Vedadi,2 Rima Al‐awar.1* 1
Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Ave, Suite 510, Toronto, Ontario, M5G 0A3, Canada and 2Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, Ontario, M5G 1L7, Canada. Histone methylation is a key component of epigenetic signaling and transcriptional regulation. The Mixed Lineage Leukemia (MLL) genes encode a family of histone methyltransferases that activate gene expression through the methylation of histone H3 on lysine 4 (H3K4). Rearrangement and amplification of the MLL1 locus are drivers of leukemogenesis, accounting for 10% of AML in adults and nearly 70% of ALL in infants. In addition, MLL1 mutations are common in a variety of solid cancers, including breast, colon, lung, and bladder. WD40 repeat protein 5 (WDR5) is a component of the multiprotein MLL1 complex that is essential for its methyltransferase activity, and disruption of the WDR5/MLL1 interaction may therefore present a viable therapeutic option for the treatment of MLL‐dependent leukemias. We conducted a medium throughput screen that identified micromolar drug like hits. Following several rounds of optimization using a structure‐based approach and focused virtual library design we were able to identify OICR‐9429, a nanomolar, highly selective and cell permeable inhibitor of the WDR5‐MLL interaction. OICR‐9429 is the first highly potent small molecule antagonist of the WDR5‐MLL1 interaction and will serve as a valuable molecular probe for further exploration of WDR5 function. 24 The Discovery of Dot1L Inhibitors by Fragment‐Based Approaches Christoph Gaul, Frédéric Stauffer, Henrik Möbitz, Rainer Machauer, Philipp Holzer, Andrea Vaupel, Giorgio Caravatti, Clemens Scheufler, Cesar Fernandez, Martin Klumpp, Ulrich Hommel, Ralph Tiedt, Andreas Weiss, Kim S. Beyer, Keith Calkins, Michael Kiffe, Chao Chen, Hugh Zhu Novartis Institutes for Biomedical Research, Basel, Switzerland and Shanghai, China Dot1L is the only known enzyme to methylate lysine 79 of histone 3 (H3K79), with the H3K79me2 mark being associated with active transcription. Under physiological conditions, Dot1L is critical for normal hematopoiesis, however, misdirected catalytic activity (methyltransferase) is believed to be causative for certain acute leukemias. Several oncogenic fusion proteins including MLL‐ENL, MLL‐AF4 and MLL‐AF9 aberrantly recruit Dot1L to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA9) which drive the leukemic phenotype. Inhibition of the methyltransferase activity of Dot1L in MLL‐rearranged leukemias (mixed lineage leukemia, MLL) is predicted to reverse ectopic H3K79 methylation, leading to repression of leukemogenic genes (HoxA9, Meis1) and tumor growth inhibition. The recent quest for Dot1L inhibitors is spearheaded by Epizyme and culminated in the discovery of EPZ‐5676, a SAM‐competitive, nucleoside‐containing Dot1L inhibitor, which is currently being evaluated in MLL patients in Phase 1b clinical trials. The agent is administered by uninterrupted, continuous intravenous (i.v.) infusion due to its physicochemical properties. Herein, we will describe our Dot1L hit finding strategy, including biochemical, biophysical and virtual approaches, and our medicinal chemistry strategy, strongly influenced by structure‐
based design and property‐based optimization. Among other concepts, a fragment growing and linking approach as well as a fragmentation method will be discussed, leading to the discovery of structurally completely novel (non‐SAM like), orally bioavailable Dot1L inhibitors with excellent cellular activity. 25 Identification of potent, selective KDM5 inhibitors Victor S. Gehlinga, Steve Bellona, Jean‐Christophe Harmangea, Yves Leblanca, Florence Poya, Shobu Odatea, Shane Bukera, Fei Lana, Shilpi Aroraa, Kaylyn Williamsona, Peter Sandya, Richard Cummingsa, Pranoti Gangurdea, Emmanuel Normanta, Chris Baileya, Louise Bergerona, Winfred Maoc, Tommy Laic, Jiangpeng Liaoc, Xiaoping Zhengc, Xiaoli Shenc, Hongbing Yuc, Pengfei Jic, Shikun Chenc, Yongliang Zongc, Wentao Wuc, Zhenfang Qinc, Weichao Shenc, Guiyu Zhaoc, Lesley Murrayb, Pete Dragovichb, Jun Liangb, Sharada Labadieb, Birong Zhangb, Amy Gustafsonb, Navneet Alagb, Erica Jacksonb, Charles Tindellb, Mike Costab, Ted Laub, Leanne Goonb, Yichin Liub, Erica VanderPortenb, Dan Ortwineb, Roger Zhaoc, Alan Dengb, Gauri Deshmukhb, Bianca Liedererb, Liling Liub, Nina Ljumanovicb, Leslie Wangb, Yingqing Ranb, Le Anb, Jiansheng Wub, Hong Lib, Zoe Zhongb, Krista Bowmanb, Inna Zilberleybb, Till Maurerb, Gladys Boenigb, Jim Kieferb, Maia Vinogradovab, Lily Ackermanb, Marie Classonb, James E. Audiaa, Patrick Trojera, Brian K. Albrechta a
Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142 Genentech Inc., 1 DNA Way, South San Francisco, CA 94080 c
WuXi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China b
The identification of a potent, selective KDM5 inhibitor will be presented. Optimization of 1, a modestly selective screening hit, afforded CPI‐621, a highly potent inhibitor of the KDM5 family of histone lysine demethylases (KDM’s). CPI‐621 has a remarkable selectivity profile against a panel of related KDM’s and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 trimethylation (H3K4me3). In addition CPI‐621 has good ADME properties, excellent mouse PK, and could serve as a useful tool compound against the KDM5 family. 26 The Discovery of BET Bromodomain Inhibitor ABBV‐075 Keith McDaniel, Steve Fidanze, Lisa Hasvold, Dachun Liu, Robert Mantei, John Pratt, George Sheppard, Le Wang, Mai H Bui, Emily Faivre, Xiaoli Huang, Leiming Li, Xiaoyu Lin, Aparna Sarthy, Rongqi Wang, Scott Warder, Denise Wilcox, Daniel Albert, Terry Magoc, Ganesh Rajaraman, Chang Park, Andrew Petros, Sanjay Panchal, Chaohong Sun, Guowei Fang, Steven W. Elmore, Saul Rosenberg, Yu Shen, Warren Kati Oncology Discovery, Research & Development, AbbVie, North Chicago, IL 60064 Phenotypic cell‐based screening assays combined with affinity chromatography and mass‐
spectrometry identified the BET family of bromodomains as a potential target for blocking proliferation in a variety of cancer cell lines. Screening of a fragment library for binding to the 13
C‐labeled 2nd bromodomain of BRD4 using 2‐dimensional NMR identified a novel pyridazinone fragment (Kd = 130 µM). An X‐ray structure enabled medicinal chemistry program provided a functionalized pyrrolopyridone core with roughly 100,000‐fold improved binding affinity. Potencies in antiproliferative and cell‐based target engagement assays correlated strongly, suggesting that antiproliferative effects resulted from the inhibition of BRD4/BET protein function. In vitro metabolite ID studies guided additional SAR studies that provided ABBV‐075, a molecule that exhibited an excellent PK profile across multiple animal species. ABBV‐075 demonstrated significant tumor growth inhibition in mouse flank xenograft studies representing diverse hematological and solid tumor malignancies and currently is undergoing Phase I clinical studies. 27 Tackling inflammation with a pro‐resolution FPR2 agonist Olivier Corminboeuf Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH‐4123 Allschwil, Switzerland [email protected] The critical role of inflammatory processes in health and disease has long been recognized. Inflammation is normally terminated by resolution, but the detailed molecular mechanisms and biological events that regulate the Resolution of Inflammation (RoI) remain largely unknown. Lately, it has been shown that the RoI, once believed to be a passive process, is in fact an active and delicately orchestrated process that can be modulated by specific receptors, such as the class A G‐Protein Coupled Receptor (GPCR) FPR2/ALXR. FPR2/ALXR is a promiscuous receptor modulated by lipids as well as by peptides, making it a rather unusual GPCR. Depending on the ligand and its resulting signaling, its activation translates in effects ranging from pro‐inflammatory, anti‐inflammatory to pro‐resolution, resulting in potent opposite effects. This versatile role renders this GPCR an attractive therapeutic target to modulate neuroinflammation. The aim of this presentation is to introduce the audience to the RoI concept and highlight Actelion’s efforts to develop small molecules to resolve inflammation by activation of FPR2/ALXR. Proof of concept studies with potent and selective FPR2/ALXR agonists will be presented followed by lead optimization that allowed for efficacy studies in mouse models. 28 Development of PET Radiotracers for Imaging Alpha Synuclein Aggregates in Parkinson’s Disease and Other Neurodegenerative Disorders Robert H. Mach Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 [email protected] One of the hallmark features of neurodegenerative disorders is the accumulation of misfolded proteins which lead to the formation of insoluble protein aggregates in the CNS. One such protein is alpha synuclein (Asyn), which serves as the major component in Lewy bodies (LBs) and Lewy neurites (LNs). LBs and LNs are the primary lesions in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Furthermore, nearly 50% of Alzheimer’s disease (AD) patients have LBs at time of autopsy, and AD patients with LBs may have a more rapid rate of cognitive decline than patients not having LB pathology. Therefore, the development of a PET radiotracer capable of imaging Asyn aggregates would provide a valuable tool in the clinical evaluation of a wide panel of neurodegenerative disorders. This presentation will describe the challenges in developing a PET radiotracer for imaging Asyn aggregates and the different strategies being used in accomplishing this goal. 29 The Evolution of In Vivo Efficacious BACE1 Inhibitors Daniel Oehlrich Neuroscience Medicinal Chemistry, Janssen, Pharmaceutical companies of Johnson & Johnson [email protected] Alzheimer’s disease is an insidious disease, where one of the two pathological features, led to the development of the ‘amyloid cascade’ hypothesis, which to date remains polemic due to the lack of clinical validation. Recent advances have been made with the identification of amidine and guanidine containing heterocycles, which form an ideal hydrogen bond network with the aspartyl dyad of BACE and possess vectors that optimally distribute groups within the active site. Although, this class of compound has presented many developmental difficulties, including Pgp, permeability and hERG, several amidine‐based BACE1 inhibitors have now entered clinical trials. The results of these trials are likely to validate BACE1 as a therapeutic target as well the amyloid hypothesis. The evolution of our project will be presented showing the importance of pKa control, resulting in the identification of two clinical candidates with high in vivo efficacy. 30 OGA Inhibitors as a Potential Disease Modifying Approach for Alzheimer Disease: Structure‐
Activity Relationships of OGA Inhibitors David Vocadlo Departments of Chemistry and Molecular Biology and Biochemistry Simon Fraser University, 8888 University Drive, Burnaby, BC Canada, V5A 1S6 [email protected] O‐linked N‐acetylglucosamine (O‐GlcNAc) was first discovered 30 years ago and is now recognized as a common form of protein O‐glycosylation found in the nucleus and cytoplasm of multicellular eukaryotes. This reversible modification is regulated by only two enzymes; O‐
GlcNAc transferase (OGT) installs this modification whereas O‐GlcNAcase (OGA) removes O‐
GlcNAc from proteins. Recently, impaired brain metabolism has been linked to altered brain O‐
GlcNAcylation in Alzheimer Disease (AD) patients, stimulating interest in OGA inhibitors as a potential therapeutic disease modifying strategy for AD. Here we will discuss our research focused on the rational design of mechanism‐inspired OGA inhibitors. Some of these tight binding transition state analogues have ligand efficiencies (LE) reaching 0.85 kcal/mol/heavy atom and exhibit selectivities for OGA of over 1 million‐fold. Chronic administration of OGA inhibitors in preclinical tauopathy animal models shows OGA inhibition is well tolerated, leading to increased brain O‐GlcNAcylation that correlates with decreased tau pathology. 31 The discovery of novel small molecule antimalarials through a global network of partnerships James Duffy Medicines for Malaria Venture (MMV) (Geneva, Switzerland) [email protected] Despite recent advances in treatment, malaria remains a worldwide health challenge. Approximately 214 million malaria cases were estimated to occur in 2015, leading to 438,000 deaths, the majority of whom were children. In addition, the increasing resistance to existing therapies highlights the need for new, affordable and safe drugs. Working together with its partners, Medicines for Malaria Venture (MMV), a not‐for‐profit, product development partnership (PDP), have established a strong anti‐malarial drug pipeline with over 15 compounds in clinical development. The presentation will discuss some of the challenges and opportunities in antimalarial drug discovery with particular focus on the case history of MMV’s successful collaboration with the University of Capetown (UCT). The UCT collaboration has resulted in the identification multiple series with potent antimalarial activity, most notably a series of aminopyridines that led to the discovery of MMV390048. MMV390048, a plasmodium PI4K inhibitor, has activity against multiple stages of the parasite life‐cycle with potential for a single dose asexual blood stage cure and is currently in Phase I and human volunteer challenge studies. 32 Leveraging foundation, corporate and NIH support for academic drug discovery Craig Lindsley Vanderbilt University This lecture will provide an overview of the Vanderbilt Center for Neuroscience Drug Discovery, focusing on how the Center was established and maintained – both challenges and opportunities. I will discuss why we elected to focus on allosteric modulation of GPCRs and how we interact with corporate partners (both biotech and Big Pharma) and the structure of licensing and sponsored research. Another major focus of support to bridge the ‘valley of death’ rests with foundations and ‘venture philanthropy’. Finally, I will showcase an example from HTS to IND‐enabling studies for a challenging target with a corporate partner, and another with a combination of NIH and Foundation support. Overall, I will discuss how a parallel deep basic science effort, coupled with traditional drug discovery, has enabled successful identification of clinical candidates, while overcoming target‐related nuances. 33 Open Innovation Drug Discovery Program: For Scientists by Scientists. MAKING LIVES BETTER TOGETHER. Julia M. Clay, Christopher Beadle, and Maria Alvim‐Gaston* Open Innovation Drug Discovery, DCR&T, Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, IN 46225 The Lilly Open Innovation Drug Discovery (OIDD) Program is founded on the belief that pharmaceutical companies, research institutions and academia share a mutual desire to advance innovative biomedical science. OIDD was created for scientists by scientists as a premier collaborative platform that unites global investigators with Lilly scientists in a hypothesis‐driven approach to early drug discovery. Through their interaction with OIDD, participants have the opportunity to contribute to the discovery of novel therapeutics, while they obtain access to cutting‐edge research tools and data that can also help them advance their own scientific work. At all times, participants retain complete control of their intellectual property. Current program offerings include computational structure design tools, in vitro compound screening, access to automated synthesis capabilities and the opportunity to contribute to research in neglected and tropical diseases such as tuberculosis and malaria. 34 Integrating OIDD into an Academic Research Program: Identification of Novel GLP‐1 Secretagogues and their Biological Target Jimmy Wu,1 George G. Holz,2,3 Chepurny,2 Colin A. Leech,2 Martin Tomanik,1 Maria C. DiPoto,1 Hui Li,1,† Xinping Han,1,†† Qinghe Meng,4 and Robert N. Cooney4 Departments of Medicine2, Surgery4, and Pharmacology3, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA; Department of Chemistry1, Dartmouth College, Hanover, New Hampshire, USA; †Current Address: Snapdragon Chemistry, Cambridge MA 02140; ††Current Address: Department of Biochemistry, UT Southwestern, Dallas TX 75390 GLP‐1 is an incretin hormone that has been validated as a target for the treatment of type 2 diabetes mellitus (T2DM), a disease that affects nearly 350 million people worldwide with a global cost of over $600 billion dollars. When bound to its receptor on the  cells of the pancreas, GLP‐1 promotes the secretion of insulin, thereby lowering blood glucose. It also slows gastric emptying and suppresses appetite, so is a potential drug for the treatment of morbid obesity. Its activity is highly dependent on the presence of glucose; therefore, T2DM therapeutics based on this pathway are less prone to causing hypoglycemia. Several GLP‐1 mimetics have either gained regulatory approval or are in clinical trials (i.e., Byetta, Victoza), but these require inconvenient daily injections. Drugs that slow the breakdown of GLP‐1 such as (i.e., Januvia) are also available. We, and others, have proposed that GLP‐1 secretagogues, alone or in combination with drugs that inhibit the breakdown of GLP‐1, can be used as effective treatments for T2DM. Despite intense interest from the pharmaceutical and biotech communities, there currently exists no approved drugs based on the up‐regulation of GLP‐1 release. We expect that orally administered GLP‐1 secretagogues would constitute an entirely new class of blood glucose‐
lowering agents. This lecture will summarize how our partnership with Eli Lilly’s OIDD program and other academic collaborative efforts lead to the discovery of GLP‐1 secretagogues and the identification of the TRPA1 receptor as its cellular target. 35 Pharmaceutical Patent Prosecution Primer and Small Molecule Obviousness Elizabeth T. Karnas Lathrop & Gage LLP http://www.lathropgage.com/ekarnas The pharmaceutical patenting process includes identifying an invention, writing a patent application that protects that invention, and prosecuting the application before the U.S. Patent Office (and patent offices throughout the world). A basic understanding of this process is a must for any scientist (academic, industrial, or otherwise). This talk will begin with an overview of our current patent laws, and demonstrate how those laws are applied to a variety of pharmaceutical innovations, such as novel chemical entities and formulations. The talk will then touch upon recent Federal Circuit decisions related to small molecule pharmaceutical obviousness, including a discussion of the “lead compound analysis.” By understanding the Federal Circuit’s position with respect to this issue, the chemistry practitioner will be equipped with the most current tools for pursuing pharmaceutical patent applications. 36 Inhibitors of Protein‐Protein Interactions: Reflections and Projections Michelle Arkin Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, School of Pharmacy, University of California, San Francisco Protein‐protein networks are critical regulators of health and disease, yet are widely considered “undruggable” or, at best, “challenging.” Thus, there is an opportunity to greatly expand the range of chemical tools and drugs if we can identify which protein‐protein interactions (PPI) are most amenable to small‐molecule interference and what small‐molecule discovery approaches are most likely to yield potent and selective modulators. This presentation will reflect on the past 10+ years of PPI inhibitor discovery, and will introduce some of our forays into challenging targets. We favor combining a variety of approaches, including fragment‐based ligand discovery, computation, and screening. Our long‐term goal is to understand the molecular recognition features that lead to binding to dynamic interfaces and to develop inhibitors of these challenging targets. 37 PROTACS: Induced Protein Degradation as a Therapeutic Strategy Craig M. Crews Departments of Chemistry; MCDB; Pharmacology, Yale University, New Haven, CT [email protected] The current ‘inhibitor/binder‐based’ paradigm of pharmaceutical control has inherent limitations: 1) the need to achieve/maintain high systemic exposure to insure sufficient in vivo protein inhibition, 2) potential off‐target side effects due to high in vivo concentrations, and 3) the need to bind to an active site, thus limiting the potential ‘drug target space’ to a fraction of the proteome. Alternatively, induced protein degradation lacks these limitations. Based on an ‘Event‐driven’ paradigm, this approach offers a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins. This is achieved via recruitment of target proteins to the cellular quality control machinery, i.e., the Ubiquitin/Proteasome System (UPS) using PROTACs (Proteolysis Targeting Chimeras) that can achieve ‘degradation concentrations’ (DC50 values) in the picomolar range. This knockdown technology has been shown to effectively decrease intracellular levels of a variety of target protein classes, including kinases, transcription factors and epigenetic readers. 38 Discovery of Ivacaftor, a CFTR Potentiator for the Treatment of Cystic Fibrosis Jinglan Zhou Vertex Pharmaceuticals Incorporated, La Jolla, CA Cystic fibrosis (CF) is a life‐threatening genetic disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Ivacaftor (VX‐770), a CFTR potentiator, is the first therapeutic agent approved by the FDA for the treatment of CF that targets the underlying molecular defect. This presentation will describe the discovery and development efforts in medicinal chemistry, formulation, pharmacokinetics, and pharmacology that transformed a high‐throughput screening hit (HTS 1) into ivacaftor (see figure). Ivacaftor is approved to treat patients with CF aged 2 years and older who have the G551D mutation and nine other mutations that affect the gating function of the CFTR protein. Sponsored by Vertex Pharmaceuticals Incorporated 39 NaV1.7 Inhibitory Peptides from Tarantula Venom: Engineering Potency and Selectivity Towards Developing Novel Pain Therapeutics Kaustav Biswas Hybrid Modality Engineering, Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA 91320 Peptides isolated from venom of poisonous species have provided important insights into ion channel biology including gating, function, and structure. To identify novel inhibitors of the voltage‐gated sodium channel NaV1.7, important for action potential generation in nociceptors and pain signalling, venom collections were screened and active peptides were discovered. They are members of the inhibitory cystine knot structural family and inhibit both expressed human NaV1.7 and endogenous tetrodotoxin‐sensitive (TTX‐S) NaV currents recorded from mouse dorsal root ganglion neurons. This presentation will describe initial peptide characterization and SAR studies to improve potency and selectivity against other NaV channels. Mapping of a functional peptide interaction site using NaV channel chimeras and effect of peptides on endogenous NaV currents in C‐fiber action potential firing in an ex vivo skin nerve prep will be shown. Finally, evidence for NaV1.7 target engagement by peptides in vivo using a histamine scratch model will be presented. 40 Poster Presentations 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Total Synthesis of Neuroprotective Agents Against Stroke. Ghina’a I. Abu Deiab (University of North Carolina at Greensboro) Open Innovation Drug Discovery Program: For Scientists by Scientists. MAKING LIVES BETTER TOGETHER. Maria Alvim‐Gaston (Eli Lilly and Company) Development of novel CXCR4 modulators by a unique FRESH program. Renren Bai (Emory University School of Medicine) Synthesis of Amphipathic 1,2,3‐triazoles and Screening for Antimicrobial, Anti‐biofilm and Anti‐oxidative Activities. Thomas A. Bakka (Norwegian University of Science and Technology) Synthesis and SAR of Indoline Sulfonyl Azide‐Derived NDM‐1 Inhibitors. Daniel P. Becker (Loyola University Chicago) Inhibitors of glucose transport as anticancer agents. Stephen C. Bergmeier (Ohio University) The Synthesis of “Clickable” Cofactor Analogs for use in Assay Development. Mark Betson (Peakdale Molecular) Design and synthesis of biologically active carboxylesterase inhibitors based upon the tanshinone scaffold for modulation of esterified drug metabolism. Randall J. Binder (St. Jude Children’s Research Hospital) Understanding the structure‐permeability relationship of semi‐peptidic macrocycles. Emilie Blaise (Université de Sherbrooke) Antibacterial activity and antiquorum sensing potential of triterpenes and flavonoids from Senegalia nigrescens. Olusola Bodede (University of KwaZulu‐Natal) Discovery of MK‐8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group. Christopher J. Bungard (Merck Research Laboratories) CREB Binding Protein (CBP) Inhibition and Target Engagement. Eugene L. Piatnitski Chekler (EMD Serano) Polyaspartate Conjugated Statin Derivative as a Potential Bone Formation Agent. Hui‐
Ting Chen (Kaohsiung Medical University) Discovery of 5‐Aryl‐2,4‐diamino‐Pyrimidine Compounds as Potent and Selective IRAK4 Inhibitors. Yan Chen (Rigel Pharmaceuticals, Inc.) 41 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Design, Synthesis and Microbiological Evaluation of Ampicillin ‐ Tetramic acid Hybrid Antibiotics. Philip T. Cherian (St. Jude Children’s Research Hospital) Design and Synthesis of Chemical Probes Targeting MLL1 Methyltransferase. Ting‐Rong Chern (University of Michigan) Macrocycle inhibitors of IDO revealed through DNA‐encoded libraries. William Connors (Ensemble) Antibody‐Maytansinoid Conjugates Utilizing Cleavable Peptide Linkers. Juliet Costoplus (ImmunoGen, Inc.) Structure‐Activity Relationship for the Discovery of Non‐electrophilic Nrf2 Activators. Brian P. David (University of Illinois at Chicago) Design and Development of Novel Herpesvirus Entry Inhibitors Directed at the Glycoprotein B (gB) Fusion Protein. Hemantkumar Deokar (Rosalind Franklin University of Medicine and Science) Is it actually worth calculating binding affinity? Carsten Detering (BioSolveIT) Making the chemical universe more accessible: de novo design 2.0. Carsten Detering (BioSolveIT) Tumour selective delivery of poly(ADP‐ribose)polymerase‐1 (PARP1) inhibitors. Benjamin D. Dickson (University of Auckland) Addressing Challenges of Low Clearance in Drug Discovery. Li Di (Pfizer) Lipophilic Isosteres of a π‐π Stacking Interaction: New Inhibitors of Bcl‐2‐Bak Interactions. Michael Doré (Novartis) Evaluation of [18F]‐RAGER: a small molecule PET ligand for the Receptor for Advanced Glycation Endproducts. Lindsey Drake (University of Michigan) Development of MK‐8719, a Novel Inhibitor of OGA for the Treatment of Tauopathies, Utilizing [18F]MK‐8553 as a Target‐Selective PET Tracer. Joseph L. Duffy (Merck Research Laboratories) Discovery of a Novel Series of Aminoquinoline Glucagon Receptor Antagonists. David C. Ebner (Pfizer) Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone‐based sulfonamide derivatives. Tamer A. El‐Waei (Cairo University) Investigation of Effect of N‐Substituents on Delta Opioid Receptor Inverse Agonism. Hideaki Fujii (Kitasato University) Modulating the eIF4E‐4E‐BP Protein‐Protein Interaction in Cancer. Erin Gallagher (University of Michigan) Development of novel positive allosteric modulators for the mGlu1 receptor: improving the pharmacokinetic profile of lead series VU0486321. Pedro M. Garcia‐Barrantes (Vanderbilt) Design and Synthesis of Small Molecule Inhibitors for β‐Catenin/T‐Cell Factor Protein‐
Protein Interactions. Wenxing Guo (University of Utah) 42 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Effect of resveratrol on sarcoplasmic reticulum Ca2+‐ATPase 2 gene expression in in cardiomyocytes subjected to oxidative stress. Abigail Guzmán‐Bárcenas (Universidad Nacional Autónoma de México) Chemical control of cullin neddylation through inhibition of the DCN1‐UBC12 interaction. Jared T. Hammill (St. Jude Children’s Research Hospital) Design, biological activity and ADME properties of pyrrolopyrimidine‐based EGFR‐TK inhibitors. Jin Han (Norwegian University of Science and Technology) Discovery of Small Molecule Enzyme Inhibitors of E. coli IspD. Brian Hartnett (Northern Illinois University) Investigation of 2‐methylpyrrole compounds as BET bromodomain inhibitors for the treatment of cancer. Lisa A. Hasvold (AbbVie) Discovery and SAR development of pyridone and pyridazinone bromodomain inhibitors. John K. Pratt (AbbVie) Discovery and SAR of novel pyrrolopyridones as BET inhibitors. Dachun Liu (AbbVie) Novel, Covalent Inhibitors of EGFR: Identification of Aminopyrazine Benzimidazoles that Selectively Target Mutant Forms of the Receptor. Edward J. Hennessy (AstraZeneca) Development of Novel μ‐/δ‐Opioid Receptor Analgesics with Reduced Tolerance and Dependence. A. Nastase and S. Henry (University of Michigan) Development of 1H‐Pyrazolo[3,4‐b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators. Matthew D. Hill (Bristol‐Myers Squibb) Synthesis and Biological Evaluation of HK‐2 Inhibitor. Imelda Hot (University of Illinois at Chicago) Development of Cancer Stem Cell Depleting ALDH1A Selective Inhibitors as Potential Therapeutics for Ovarian Cancer. Brandt C. Huddle (University of Michigan) Identification of GNE‐131: A potent and selective hNaV1.7 inhibitor for the treatment of pain. Fred Hu (ChemPartner) Evaluation of 2‐aminobenzothiazoles (BET) as potent inhibitors of Mycobacterium tuberculosis. Jo‐Ann Jee (Infectious Disease Research Institute) Novel synthetic ligands for REV‐ERBα: The role of circadian drug discovery targets in pulmonary inflammation. Understanding the rhythm of pulmonary inflammation. D. Heulyn Jones (University of Strathclyde) A novel rabbit‐derived peptide as potent analgesics. Chai‐Lin Kao (Kaohsiung Medical University) The Discovery of Novel Scaffolds as NR2B Receptor Negative Allosteric Modulators. George N. Karageorge (Bristol‐Myers Squibb) Design, Synthesis and Screening of Triaminopyrimidine Analogs as Inhibitors of Inflammatory Caspases. Caitlin Karver (DePaul University) Inhibitors of the ubiquitin ligase Nedd4‐1 discovered by covalent fragment screening. Stefan Kathman (Northwestern University) 43 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 Imidazopyridine Inhibitors of Dual Leucine Zipper Kinase (DLK) for Neurodegenerative Indications. Terry Kellar (Genentech) Blocking Bleach Production with Reversible Inhibitors of Myeloperoxidase. Ellen Kick (Bristol‐Myers Squibb) A Rapid Experimental Polar Surface Area (EPSA) Assay. J. P. Kiplinger (Averica Discovery Services) Design, synthesis and biological evaluation of N4‐phenylsubstituted‐7H‐pyrrolo[2,3‐
d]pyrimidin‐4‐amines as multi‐targeted anticancer agents targeting EGFR, JAK2 and AURKA. Sonali Kurup (Roosevelt University) Discovery of Substituted (4‐phenyl‐1H‐imidazol‐2‐yl)methanamine as Potent Somatostatin Receptor 3 Agonists. Zhong Lai (Merck Research Laboratories) Design and SAR of Next Generation of Potent, Selective, and Non‐covalent BTK Inhibitors. Wendy Lee (Genentech) Identification of Novel Constrained Peptides Which Exhibit Glucagon‐Like Peptide‐1 Receptor (GLP‐1R) Agonism. Chris Limberakis (Pfizer) Synthesis, Identification and Biological Evaluation of 20S,23S‐Dihydroxyvitamin D3 as a Natural Vitamin D3 Metabolite of CYP11A1. Zongtao Lin (University of Tennessee Health Science Center) Discovery of Orally Bioavailable and Liver Targeted Hypoxia‐Inducible Factor Prolyl Hydroxylase (HIF‐PHD) Inhibitors for Anemia. Ping Liu (Merck Research Laboratories) Development of a selective inhibitor targeting the BRG1/BRM bromodomain. Yangbing Li (University of Michigan) Discovery of Dual‐Action Inhibitors Targeting Histone Deacetylases and Cyclin D Kinase 4/6 against Malignant Diseases. Yan Fan and Rong Xiang (Nankai University) Identification of Selective Ligands targeting Breast Cancer Stem Cells by Using Combinatorial Chemical Library. Chao Long (University of Texas at Dallas) Preparation and Biological Evaluation of BACE1 Inhibitors with trans‐Cyclopropylamide Linker. Jose E. Lopez (Eli Lilly and Company) Design, Synthesis, Protein Crystallography, and Biological Evaluation of BACE1 Inhibitors Using Multiple Types of Conformational Restriction to Achieve Enzyme and Cellular Potency. Warren J. Porter (Eli Lilly and Company) Synthesis, molecular docking study and in vitro anticancer activity of tetrazole linked benzochromene derivatives. Suresh Maddila (University of KwaZulu‐Natal) Novel Mcl‐1 selective small‐molecule inhibitors as a promising targeted therapy for multiple myeloma. Ahmed Mady (University of Michigan) Avoiding Missed Opportunities by Analysing the Sensitivity of our Decisions. Tamsin E. Mansley (Optibrium Ltd) Development of Selective Inhibitors of Aggrecanase 1 and 2 for the Treatment of Osteoarthritis: Exploitation of Structural Features in the S1’ Site to Achieve Selectivity. Jothiraja Marimuthu (Eli Lilly and Company) 44 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 Unsymmetrical Nutlin‐3a analogs for treatment of retinoblastoma. Anand Mayasundari (St. Jude Children’s Research Hospital) Design, synthesis and application of novel building blocks to “Escape the Flatland” in medicinal chemistry. Pavel Mykhailiuk (Enamine Ltd) Synthesis and application of unnatural Proline analogues: advanced building blocks for medicinal chemistry. Pavel Mykhailiuk (Enamine Ltd) Discovery of MK‐8831, A Novel Spiro‐proline Macrocycle as a Pan‐Genotypic HCV‐
NS3/4a Protease Inhibitor. Santhosh F. Neelamkavil (Merck Research Laboratories) Synthesis and Behavioral Studies of Chiral Cyclopropanes as Selective α4β2‐Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Oluseye K. Onajole (Roosevelt University) Developing Small Molecule Activators for Ring‐Between‐Ring E3 Ubiquitin Ligase PARKIN. Sungjin Park (Northwestern University) Molecular design and synthesis of chromenopyridines as anti‐fibrotic agents. Shivaputra Patil (Rosalind Franklin University of Medicine and Science) Fingolimod Phosphoroamidate Prodrugs for potential treatment of Multiple Sclerosis. Fabrizio Pertusati (Cardiff University) Copper‐catalysed diastereoselective synthesis of P‐chiral phosphoramidate prodrugs (ProTides). Elisa Pileggi (Cardiff University) Tumor‐Targeting Alkyl Phospholipid‐Drug Conjugates. Anatoly Pinchuk (Cellectar Biosciences) Development of Oxidative stress inducing, GSTP1 inhibiting BBB penetrable small molecule and evaluation in glioblastoma models in vitro and in vivo. Surendra R. Punganuru (Texas Tech University Health Sciences Center) Development of Novel Inhibitors of the Key Shigella Flexneri Virulence Regulator. Nicholas J. Ragazzone (University of Michigan) Chemoproteomic Probes for the Keap1/Nrf2 Interaction. Benjamin Richardson (University of Illinois at Chicago) Identification and Evaluation of Isothiazole‐Based Novel Nrf2 inducers. Fumihiko Saitoh (Mochida Pharmaceuticals) Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase‐
Activating Compound 1 (PAC‐1) with Improved Pharmacokinetics. Howard S. Roth (Yale University) New therapeutic agents for tuberculosis: Synthesis, SAR and pharmacological evaluation of pyrazolo[1,5‐a]pyrimidin‐7‐ols. Shaik Azeeza (National Institutes of Health) A Novel Dendrimer‐Curcumin Formulation. A. Sharma (Central Michigan University) LipE‐Guided Discovery and Development of Pantothenate Kinase Modulators. Lalit Kumar Sharma (St. Jude Children’s Research Hospital) Evaluation of A Novel and Potent Uricosuric Agent. Dongfang Shi (Jiangsu Atom Bioscience and Pharmaceutical Co. Ltd) 45 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 Benzbromarone Analog As a Potent Uricosuric Agent for the Treatment of Gout. Dongfang Shi (Jiangsu Atom Bioscience and Pharmaceutical Co. Ltd) Design and Syntheses of Novel Fluorescent and Biotinylated Tocopherol Probes. Zhen‐
Dan Shi (National Institutes of Health) Discovery of Purine‐based Inhibitors of Dual Leucine Zipper Kinase (DLK) for Neurodegenerative Indications. Daniel G. M. Shore (Genentech) Synthesis, Docking and Antidiabetic Activity of Some Newer Benzamide Glucokinase Activators. Ajmer Singh (Devi Lal Memorial College of Pharmacy) Inhibitors of HIV‐1 Maturation: Exploration of structure‐activity relationship (SAR) of C‐
28 amines, based on C‐3 benzoic acid‐modified triterpenoids. Sing‐Yuen Sit (Bristol‐
Myers Squibb) Branching Out: γ‐Methylated Hydrocarbon Stapled Peptides for the Estrogen Receptor/Coactivator Interaction. Thomas E. Speltz (University of Illinois at Chicago) Neuro‐imaging using Positron Emission Tomography. Alexandra R. Sowa and Megan N. Stewart (University of Michigan) Discovery of a series of noncompetitive beta‐secretase (BACE1) inhibitors with the assistance of STD‐NMR. Deyang Sun (Chinese Academy of Medical Sciences) The Identification of (R)‐(2‐chloro‐3‐(trifluoromethyl)phenyl)(1‐(5‐fluoropyridin‐2‐yl)‐4‐
methyl‐6,7‐dihydro‐1H‐imidazo[4,5‐c]pyridin‐5(4H)‐yl)methanone (JNJ 54166060), a small molecule antagonist of the P2X7 receptor. Devin M. Swanson (Janssen Pharmaceutical Research & Development) Quinoline Modulators of RORt. Virginia Tanis (Janssen Pharmaceutical Research & Development) Structural Requirements for Indolyl‐Pyridinyl‐Propenones to Induce Either Methuosis, Microtubule Disruption or Cytoplasmic Vacuolization. Christopher J. Trabbic (University of Toledo) Quinoline‐Based P2‐P4 Macrocyclic HCV NS3/4A Protease Inhibitors with pan‐genotypic activity. Francisco Velázquez (Merck Research Laboratories) Pyridopyrimidinone‐Core Subseries as Highly Selective and Brain‐Penetrant Alternative to GNE‐0723, a GluN2A‐Selective NMDA Receptor Positive Allosteric Modulators (PAMs). Elisia Villemure (Genentech) Crystal structures of large, multi‐domain, catalytically active KDM5a fragments reveal inhibitor mechanism of selective drug CPI‐455. Maia Vinogradova (Genentech) Design and characterization of thiol modified 5‐methylcytosine containing oligonucleotide: A potential Z‐DNA forming probe. Vorasit Vongsutilers (Chulalongkorn University) Development and Structural Evaluation of Potent and Selective G‐protein Coupled Receptor Kinase 2 Inhibitors. Helen V. Waldschmidt (University of Michigan) Discovery and Optimization of Quinoxaline‐pyrrolodihydropiperidinones as Potent Pim‐
1/2 Kinase Inhibitors. Hui‐Ling Wang (Amgen Inc.) 46 107 (Poster withdrawn) 108 Discovery and Optimization of Chitinase inhibitors. Libo Xu (Merck Research Laboratories) 109 Covalent inhibitors of the bacterial glycosyltransferase LgtC. Yong Xu (King's College London) 110 Benzimidazole analogs target Methicillin Resistant Staphylococcus aureus and inhibit WTA biosynthesis. Shu‐Wei Yang (Merck Research Laboratories) 111 Identification and optimization of potent, selective and cellularly‐active KDM5 inhibitors. Birong Zhang (Genentech) 47 Poster #1 Total Synthesis of Neuroprotective Agents Against Stroke Ghina’a I. Abu Deiab; Mitchell P. Croatt University of North Carolina at Greensboro, Greensboro, NC [email protected] , [email protected] We present our step‐economical synthesis of isocarbacyclin and analogues. Isocarbacyclin is a valuable target due to its neuroprotection from the oxidative damage after a stroke. Specifically, we utilized a palladium‐catalyzed decarboxylative coupling of a pentadienyl dienoate, a rhodium‐catalyzed diene‐diene [2+2+1] cycloaddition, and a ruthenium‐catalyzed cross‐metathesis reaction. The decarboxylation reaction is the first decarboxylation of its type since the carboxyl‐bearing carbon does not possess an anion‐stabilizing group. The diene‐diene [2+2+1] cycloaddition is the first cyclocarbonylation between two dienes. The metathesis reaction is particularly valuable since it allows for late‐stage diversification. These three metal‐
catalyzed reactions enabled us to complete the synthesis of isocarbacyclin in nine steps, seven for some analogues, instead of the 15 or more steps that have been previously reported. 48 Poster #2 Open Innovation Drug Discovery Program: For Scientists by Scientists. MAKING LIVES BETTER TOGETHER. Julia M. Clay, Christopher Beadle, and Maria Alvim‐Gaston* Open Innovation Drug Discovery, DCR&T, Lilly Research Laboratory, Eli Lilly and Company Indianapolis, IN 46225 The Lilly Open Innovation Drug Discovery (OIDD) Program is founded on the belief that pharmaceutical companies, research institutions and academia share a mutual desire to advance innovative biomedical science. OIDD was created for scientists by scientists as a premier collaborative platform that unites global investigators with Lilly scientists in a hypothesis‐driven approach to early drug discovery. Through their interaction with OIDD, participants have the opportunity to contribute to the discovery of novel therapeutics, while they obtain access to cutting‐edge research tools and data that can also help them advance their own scientific work. At all times, participants retain complete control of their intellectual property. Current program offerings include computational structure design tools, in vitro compound screening, access to automated synthesis capabilities and the opportunity to contribute to research in neglected and tropical diseases such as tuberculosis and malaria. 49 Poster #3 Development of novel CXCR4 modulators by a unique FRESH program Renren Bai1, Qi Shi2, Zhongxing Liang1, Younghyoun Yoon1, Hyunsuk Shim1,3,4,* 1
Department of Radiology and Imaging Science, Emory University School of Medicine, Atlanta, GA 30322, USA; 2Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA; 3Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA 4
Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA [email protected], [email protected] CXCR4 plays crucial roles in the recruitment of inflammatory cells to the inflammation site at the beginning of disease process. Modulating CXCR4 function presents a new avenue for anti‐
inflammatory strategy. A novel computer‐aided drug design program, FRESH workflow, was used for anti‐CXCR4 lead compound discovery and optimization. Results: Out of 30 top‐ranked amide‐sulfamide compounds that were obtained after systemic filtering and docking screening, twelve compounds were synthesized and all exhibited promising binding affinity and anti‐
invasion effect. Compounds Ig and Im showed notable in vivo anti‐inflammatory activity. Conclusion: Our data demonstrated that the FRESH program could successfully find additional potent lead compounds, and the amide‐sulfamide structure is a novel and effective pharmacophore blocking CXCR4. 50 Poster #4 Synthesis of Amphipathic 1,2,3‐triazoles and Screening for Antimicrobial, Anti‐biofilm and Anti‐oxidative Activities Thomas A. Bakkaa, Morten B. Strømb, Jeanette H. Andersenc and Odd R. Gautuna a
Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO‐7491 Trondheim, Norway; bDepartment of Pharmacy, Faculty of Health Sciences, University of Tromsø, NO‐9037 Tromsø, Norway; cMarbio, Faculty of Biosciences, Fisheries and Economics, University of Tromsø, NO‐9037 Tromsø Norway [email protected] We have synthesized a series of small 1,4‐substituted 1,2,3‐triazoles in order to probe a variety of functional groups towards antimicrobial activity. The basis of antimicrobial activity for these compounds stems from a decremented pharmacophore model based on antimicrobial peptides.1‐3 By utilizing simple “Click”‐chemistry,4,5 we have conveniently created a series of compounds with different polar nitrogen groups and non‐polar aromatic groups, in addition to a small variation in chain “length” (1 carbon). Of the 24 compounds synthesized; 4 structures showed promising activity and were subjected to dilution assays. The most potent compound displayed moderate minimum inhibitory concentrations (MIC) of 24.6‐98.3 µM against Streptococcus agalacticae, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and, Enterococcus efaecalis. Also, of the 24 compounds; 6 showed biofilm inhibiting effects, and 3 showed antioxidant properties at the tested concentrations. In addition, all of the compounds synthesized displayed a low toxicity against human erythrocytes. (1) Strøm, M. B.; Haug, B. E.; Skar, M. L.; Stensen, W.; Stiberg, T.; Svendsen, J. S. J. Med. Chem. 2003, 46, 1567 (2) Hansen, T.; Alst, T.; Havelkova, M.; Strøm, M. B. J. Med. Chem. 2009, 53, 595. (3) Hansen, T.; Ausbacher, D.; Flaten, G. E.; Havelkova, M.; Strøm, M. B. J. Med. Chem. 2011, 54, 858. (4) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004. (5) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem 2002, 67, 3057. 51 Poster #5 Synthesis and SAR of Indoline Sulfonyl Azide‐Derived NDM‐1 Inhibitors 1
1
1
Cory Reidl , Maxwell Moore , Iman Darwish , Alesha Stewart2, Pei W. Thomas2, Walter Fast2, Daniel P. Becker*1 1
Department of Chemistry and Biochemistry, Loyola University Chicago, Chicago, IL 60660; 2Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712 [email protected] New Delhi Metallo‐β‐Lactamase 1 (NDM‐1) is a zinc‐dependent metallohydrolase found in bacteria that confers resistance to commonly‐administered antibiotics, including penicillins, cephalosporins, and carbapenems. The prevalence of NDM‐1 globally combined with the ease with which the gene for NDM‐1 is transferred between various strains of bacteria poses a serious threat to modern medicine. Inhibiting NDM‐1 should restore the efficacy of β‐lactams, which are among the most commonly used antibiotics. We have employed copper(I)‐catalyzed couplings of sulfonyl azides and alkynes to generate a diverse set of NDM‐1 inhibitors including sulfonyl amidines, acyl sulfonamides, and sulfonyl triazoles with low‐micromolar potency. Docking suggest that these inhibitors interact with both Lewis acidic zinc atoms in the active site. Using this chemistry, we have synthesized single‐digit micromolar inhibitors of NDM‐1. In the design of potent NDM‐1 inhibitors, we have the opportunity of developing new therapeutic agents to be co‐administered with β‐lactam antibiotics, restoring their efficacy. 52 Poster #6 Inhibitors of glucose transport as anticancer agents Emma Kessler,a Johannes Diesel,a Yanrong Qian,b Pratik Shriwas,c Maximilian Munzer,a Jennifer V. Hines,a Xiaozhuo Chen,a, b Stephen C. Bergmeiera, b a
Department of Chemistry & Biochemistry, bEdison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA; cDepartment of Biological Sciences, Ohio University, Athens, OH, 45701, USA The Warburg effect, or upregulated glycolysis, is a near‐universal hallmark of cancer cells. Because of the increasing demands for biomaterials and energy generated during rapid cell proliferation, cancer cells rely on upregulating glycolysis. As a result, cancer cells are much more sensitive to changes in glucose concentration and glucose metabolism than normal cells. This makes glucose transport, the first and rate‐limiting step in glucose metabolism, a new and effective target for novel anticancer strategies and therapeutic development. We had previously reported on a series of benzoate esters as glucose transport inhibitors. These compounds showed both in vitro and in vivo activity against several cancer cell lines. We have prepared a series of bioisosteric ether derivatives containing additional functionality to create additional non‐covalent interactions with the glucose transporter. The synthesis of these unique analogs as well as in vitro activity (glucose transport, cell growth inhibition) will be reported. 53 Poster #7 The Synthesis of “Clickable” Cofactor Analogs for use in Assay Development a
a
Mark Betson , Rebecca Brimage , Gary Fairleyb, Geoff Holdgateb and Thorsten Nowakb Peakdale Molecular, UK; bAstraZeneca, UK [email protected] Assay development is a key step for project initiation in the early phase of drug discovery. Generation of suitable assay tools/ligands for novel targets is usually bespoke which has a high cost and time implication. The aim of this project was to synthesize a primary modulator toolbox based on frequently used co‐factors and non‐specific natural ligands which could be used generically across and within a range of protein families and subfamilies as primary assay validation tools. This poster describes the synthesis of a collection of analogs of enzyme cofactors such as NAD+, SAM and ATP that contain pendant acetylene units, rendering them suitable for Click chemistry reactions. The synthetic targets posed serious synthetic chemistry challenges, not least in the purification of very polar and water soluble compounds. a
Figure 1 – Examples of the synthetic targets 54 Poster #8 Design and synthesis of biologically active carboxylesterase inhibitors based upon the tanshinone scaffold for modulation of esterified drug metabolism Randall J. Binder, M. Jason Hatfield, Ellie Fratt, Richard Lee, and Phil Potter Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital [email protected] Recently, we determined that extracts of Danshen (Salvia miltiorrhiza) can inhibit carboxylesterases (CEs), resulting in reduced drug metabolism. Anticancer agent irinotecan requires these enzymes for conversion to its active metabolite. The local toxicity associated with this agent is known to be dose‐limiting. Previous results indicated that the inhibition of CEs by extracts of Danshen occurs due to the presence of naturally‐occurring tanshinones. Thus, we sought to develop novel isozyme‐specific inhibitors to selectively modulate metabolism of the administered agent. Applying a synthetic strategy based upon palladium‐
catalyzed Suzuki couplings, we have developed routes for the synthesis of analogues which possess low nM Ki values for inhibition of both liver and intestinal CEs. This facile synthetic approach has resulted in a panel of biologically‐active inhibitors that will allow for a detailed understanding of esterified drug metabolism by CEs by which dosing regimens may be improved with the aid of a co‐drug. 55 Poster #9 Understanding the structure‐permeability relationship of semi‐peptidic macrocycles a
a
a
Blaise E. , Le Roux A. , Doucet A. , Giarrusso M.a, Collin M.‐P.b, Neubauer T.b, Koelling F.b, Wittwer M.b, Hillisch A.b, Mittendorf J.b, Marsault E.a a
Laboratoire de Chimie Médicinale, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke (Qc), Canada; bBayer Pharma AG, Aprather Weg 18a, D‐42113 Wuppertal, Germany. [email protected] , [email protected] Over the past decade, the increasing complexity of therapeutic targets led to a growing interest in macrocycles, especially cyclic peptides. Indeed, reliable synthetic methodologies coupled to broad chemical diversity make them easily and rapidly accessible. Moreover, cyclisation provides conformational restrictions and relative flexibility that favourably impact pharmacokinetics and metabolic stability. Although a lot of attention has been given to understand the rules of permeability for purely peptidic macrocycles, to date there is no systematic study on structure‐permeability relationships of semi‐peptidic macrocycles. This work reports our results on understanding the features beneficial for permeability of this latter class. Toward this end, a series of 26 tripeptides tethered head‐to‐tail with simple alkyl linkers was synthesized. The permeability results (Caco‐2 and PAMPA assays) yield important insights about the influence of macrocycle size, stereochemistry, and presence or absence of beta‐
/gamma‐ amino acids, peptoids or N‐methylation. 56 Poster #10 Antibacterial activity and antiquorum sensing potential of triterpenes and flavonoids from Senegalia nigrescens Olusola Bodede1*, Shakira Shaik2, Hafizah Cheniah2, Roshila Moodley1 1
School of Chemistry, University of KwaZulu‐Natal, Westville Campus. Private Bag X54001, Durban, 4000 South Africa; 2School of Life Sciences, University of KwaZulu‐
Natal, Westville Campus. Private Bag X54001, Durban, 4000 South Africa The role played by plant – derived bioactive principles in modern drug discovery cannot be overemphasized as they provide an inexhaustible source of pharmacophoric skeletons which are usually subjected to synthetic modifications in search for novel compounds with better biological activities. Phytochemical investigation of the leaves, knobs and roots of Senegalia nigrescens resulted in the isolation of a new C‐3 ether conjugate of lupeol; lupeyltridecanoyl ether along with the known 30‐Hydroxylup‐20(29)en‐3β‐ol, 3β‐hydroxy‐20(29)‐en‐lupan‐30‐al, lupeol and stigmasterol. A diterpenoid; ent‐kaur‐15‐ene‐17,19‐diol and two flavonoids (quercetin and quercetin‐3‐O‐methyl ether) have also been identified while some others are currently being elucidated. All compounds along with the crude extracts were tested against nine bacterial strains among which is Chromobacterium violaceum, a commonly used quorum sensing indicator strain. Results revealed that some of the compounds and most of the extracts are potential chemo and phytotherapeutic candidates for the control of existing and emerging infectious diseases. 57 Poster #11 Discovery of MK‐8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group a
Christopher J. Bungard,* Peter D. Williams,a Jeanine E. Ballard,a David J. Bennett,a Christian Beaulieu,b Carolyn Bahnck‐Teets,a Steve S. Carroll,a Ronald K. Chang,a David C. Dubost,a John F. Fay,a Tracy L. Diamond,a Thomas J. Greshock,a Li Hao, M. Katharine Holloway,a Peter J. Felock, Jennifer J. Gesell,a Hua‐Poo Su,a Jesse J. Manikowski,a Daniel J. McKay,b Mike Miller,a Xu Min,a Carmela Molinaro,a Oscar M. Moradei,b Philippe G. Nantermet,a Christian Nadeau,b Rosa I. Sanchez,a Tummanapalli Satyanarayana,c William D. Shipe,a Sanjay K. Singh,c Vouy L. Truong,b Sivalenka Vijayasaradhi,c Catherine M. Wiscount,a Joseph P. Vacca,b Sheldon N. Crane,b and John A. McCauley.a a
Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA; b
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Quebec, Canada, H9H 3L1; cAlbany Molecular Research Singapore Research Center, 61 Science Park Road #05‐01, The Galen Singapore Science Park II, Singapore 117525 [email protected] A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors, of which MK‐8718 was identified as a compound with a favorable overall profile. MK‐8718 58 Poster #12 CREB Binding Protein (CBP) Inhibition and Target Engagement Eugene L. Piatnitski Chekler [email protected] Fully profiled chemical probes are essential to support the unbiased interpretation of biological experiments necessary for rigorous preclinical target validation. We believe that by developing a chemical probe tool kit, chemical biology can have a more central role in identifying targets of potential relevance to disease, avoiding many of the biases that complicate target validation. A development of CREB Binding Protein (CREBBP) selective chemical probe to elucidate biology associated with this bromodomain epigenetic target is presented. Chemical probe optimization is a strategic balance between physiochemical properties and chemistry, to identify high affinity binders that are functionally active and selective, with good permeability properties. The selectivity of the chemical probe against other bromodomain family members was investigated using biochemical and biophysical assays. To address the selectivity issue with BRD4, X‐ray crystal structures of the probe candidates bound to CREBBP and BRD4 were used to guide the design. The chemical probes were useful in studies aimed at validating CREBBP as a therapeutic target and for establishing its biological role. 59 Poster #13 Polyaspartate Conjugated Statin Derivative as a Potential Bone Formation Agent Hui‐Ting Chen,1,2* Kuang‐Chan Hsieh,3 Je‐Ken Chang,2 Zhi‐Hong Wen, 4 Mei‐Ling Ho2 1
Department of Fragrance and Cosmetic Science; 2 Orthopedic Research Center; 3 School of Pharmacy, at Kaohsiung Medical University, Taiwan; 4 Department of Marine Biotechnology and Resources, National Sun Yat‐sen University, Kaohsiung, Taiwan. [email protected] In addition to cholesterol lowing, stains have been discovers their lipid independent effects named as pleiotropic effects including bone anabolism. In terms of clinical potential, however the effective dosage in rat model experiments is exceptionally high. In human studies, it was explored to demonstrate obvious anabolic effect while locally used, but the effects on oral or systemic administration remains controversial. In this presentation, we will elucidate a bone specific derivative with bone affinity peptide, address the synthesis through solid phase approach with the assistance of microwave irradiation, and report its activity in bone targeting and induction of bone formation as well. Compares to simvastatin, this peptide conjugate shows highly potential for clinical use according to its less cytotoxicity and 150 % bone mass increase. 60 Poster #14 Discovery of 5‐Aryl‐2,4‐diamino‐Pyrimidine Compounds as Potent and Selective IRAK4 Inhibitors Yan Chen,* Rajinder Singh, Rose Yen, Nan Lin, Vanessa Taylor, Gary Park, Meagan Chan, Donald Payan Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., South San Francisco, CA 94080, USA [email protected] IRAK4 kinase plays an important role in IL‐1/TLR signaling pathway, and is one of the key receptors that regulate innate immune response which is associated with various inflammatory and cell proliferative disorders. From HTS screening and through hit‐to‐lead optimization, compounds with 5‐aryl‐2,4‐diamino‐pyrimidine structures have been identified as potent IRAK4 inhibitors. IRAK4 co‐crystal structure with an early lead molecule was obtained and was used to guide SAR analysis and new compounds design. This series of compounds also exhibit high selectivity over TAK1 kinase of which would cause liver toxicity and over‐immunosuppression if inhibited, TAK1 selectivity was found to be closely associated with different sizes and types of substituents at 5‐position of pyrimidine. A few representative compounds were evaluated in IL‐
1 induced IL‐6 inhibition animal model studies and showed modest efficacy. 61 Poster #15 Design, Synthesis and Microbiological Evaluation of Ampicillin ‐ Tetramic acid Hybrid Antibiotics Philip T. Cherian1, Aditi Deshpande2, Martin N. Cheramie1, David F. Bruhn1, Julian G. Hurdle2, 3 and Richard E. Lee1 1
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA. 2Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA. 3Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College of Medicine, Bryan, Texas, 77807, USA. [email protected] Exploiting iron‐uptake pathways by conjugating β‐lactam antibiotics with iron‐chelators such as catechol and hydroxamic acid is a proven strategy to overcome permeability‐related resistance in Gram‐negative bacteria. Since naturally occurring iron chelating tetramic acids have not been previously examined for this purpose, an exploratory series of novel ampicillin‐tetramic acid hybrids was designed and synthesized. The hybrids were less active against Gram‐positive bacteria. However, against Gram‐negative bacteria, their activity was species dependent with several hybrids displaying improved activity over ampicillin against wild‐type Pseudomonas aeruginosa. Unlike the catechol and hydroxamic acid β‐lactam conjugates, the activities of the hybrids did not improve under iron‐deficient conditions suggesting that the tetramic acid hybrids gain permeability via different membrane receptors, or they are out competed by native bacterial siderophores with stronger affinities for iron. This study provides a foundation for the further exploitation of the tetramic acid moiety to achieve novel β‐lactam anti‐Gram‐
negative agents. 62 Poster #16 Design and Synthesis of Chemical Probes Targeting MLL1 Methyltransferase 1
2
Ting‐Rong Chern, Shirley Lee, Liyue Huang. 4,6 Denzil Bernard,4,6 Yali Dou2,3, and Shaomeng Wang1,4,5,6 1
2
Departments of Medicinal Chemistry; Pathology; 3Biological Chemistry; 4Internal Medicine; 5Pharmacology; and 6Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109,United States [email protected] Rearrangements of the Mixed‐Lineage Leukemia (MLL) gene located on the chromosome 11q23 are responsible for >70% of acute lymphoblastic leukemia (ALL) in infants and ~ 10% of acute myelogenous leukemia (AML) in adults. The translocation involved in the fusion of N‐terminus MLL with other fusion partners resulted in the lost of C‐terminus SET domain, which is responsible for histone H3 lysine 4 methylation (H3K4). Studies showed that the wild‐type MLL1 also plays a significant role in the leukemogenesis, however, the detailed mechanism is still not clear. Whether methyltransferase activity is critically essential for leukemogenesis is still in debate. In this study, we have developed chemical probes targeting MLL1 methyltransferase. The utilization of this chemical probe could reveal the role of MLL1 in MLL‐fusion leukemogenesis. 63 Poster #17 Macrocycle inhibitors of IDO revealed through DNA‐encoded libraries W. Connors*, J. Bond, T. Briggs, Y. Chang, D. Dodge, S. Hale, M. Lee, R. Martinelli, K. Shortsleeves, N. Terrett Ensemble Therapeutics Corporation 99 Erie St., Cambridge, MA 02139 [email protected] Indoleamine‐2,3‐dioxygenase (IDO), an enzyme responsible for the degradation of L‐
tryptophan, has been shown to assist tumor cells avoid the immune system by depletion of this key amino acid. IDO is currently a favored target for cancer treatment. Many IDO inhibitors currently in development are heme binders, and consequently have low specificity for their target. Conformationally restricted macrocycles with molecular weights beyond the traditional ‘rule‐of‐5’ guidelines offer the advantage of binding allosterically and thus provide target selectivity. We have generated large numbers of macrocycles using DNA‐encoded technologies to yield chemically‐diverse libraries which have been screened against IDO. Many structurally‐
related families consisting of highly enriched hits were subsequently validated through individual ‘off‐DNA’ synthesis against both targets, yielding macrocycles with low nanomolar‐
range cellular potency. Ensuing medicinal chemistry efforts have led to more advanced analogs with sub‐nanomolar level potency, good cell permeability and oral bioavailability in animal models. 64 Poster #18 Antibody‐Maytansinoid Conjugates Utilizing Cleavable Peptide Linkers Juliet Costoplus, Karen Veale, Wayne Widdison, Ravi Chari , Rajeeva Singh, Anja Skaletskaya, Ling Dong, Andre Dandeneau, Rui Wu, Hans Erickson, Nate Fishkin, Luke Harris, Greg Jones, Victor Goldmacher, Yelena Kovtun, Erin Maloney, Yulius Setiady, Laura Bartle ImmunoGen, Inc. [email protected] Antibody‐drug conjugates (ADCs) consist of three components: a monoclonal antibody, a cytotoxic payload and a linker that connects the antibody to the payload. The linker must provide a stable bond allowing the ADC to remain intact during circulation. Non‐cleavable linkers, such as SMCC, connect the payload and antibody through a thioether bond. The ADC’s antibody must undergo extensive proteolysis in order to release cytotoxic metabolites. Short cleavable peptide linkers were prepared and incorporated in ADCs that require only one peptide bond of the linker to be cleaved to more efficiently release the metabolite. The cytotoxicities and other properties of ADCs with different peptide linkers were compared to SMCC‐linked ADCs. The synthesis of these linkers and results of the studies will be presented. 65 Poster #19 Structure‐Activity Relationship for the Discovery of Non‐electrophilic Nrf2 Activators Atul D. Jain, Brian P. David, Ewelina Choma, Terry W. Moore University of Illinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy [email protected] Nrf2 is one of the primary regulators of the antioxidant response, by directing the transcription of various detoxifying enzymes. Ubiquitination and subsequent degradation of Nrf2 is mediated by a substrate adaptor protein called Keap1. Activation of Nrf2 could be a promising therapeutic approach for prevention and treatment of inflammatory or oxidative stress‐related diseases. Both electrophilic and non‐electrophilic activators have been shown to interact with Keap1, leading to disruption of the Keap1/Nrf2 complex. Various electrophiles have been shown to have off‐target activities, which may be avoided with non‐electrophilic Nrf2 activators. We have developed a structure‐activity relationship around a known, naphthalene‐
based non‐electrophilic activator. The naphthalene moiety may introduce solubility and metabolic liabilities, so we undertook a “scaffold‐hopping” approach. We have synthesized a series of non‐naphthalene scaffolds to improve the physicochemical and pharmacokinetic properties of the lead, demonstrating that the naphthalene moiety is not necessary for binding to Keap1. 66 Poster #20 Design and Development of Novel Herpesvirus Entry Inhibitors Directed at the Glycoprotein B (gB) Fusion Protein Hemantkumar Deokar1*, Shannon Gallagher2, Sarah A Connolly2,3, John K. Buolamwini1 1
Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science; 2Department of Biological Sciences, DePaul University; 3Department of Health Sciences, DePaul University [email protected] Herpes viruses are DNA viruses that cause various diseases in humans and other animals. They enter into cells by fusion of the viral membrane with the host cell membrane, mediated by glycoprotein B (gB), a class III viral fusion protein that is conserved across all herpesviruses. This protein and other fusion proteins of its class are metastable proteins that mediate fusion by inserting into a target membrane and refolding from a prefusion to a postfusion conformation to bring the viral and cell membranes together. Crystal structures of the postfusiongB conformation have been solved, however its prefusion conformation and the details of how it refolds to promote fusion are unclear. A mutagenesis study demonstrated that a region in HSV gB termed the coil‐arm region, contributes to fusion. Mutations predicted to disrupt the coil‐
arm interaction reduced fusion and this phenotype could be rescued by the addition of a hyperfusogenic mutation in the gB cytoplasmic tail. This gB coil‐arm region resembles the six‐
helix bundle that is predicted to provide energy to drive fusion in class I fusion proteins. In designing compounds to target the virus gB protein, we used the X‐ray crystal structure viral protein (pdb: 2GUM) and carried out structure‐based virtual screening (docking) using a diverse chemical library. The compounds were docked at the coil‐arm region of herpes simplex virus (HSV) gB. The top 10% of the compounds ranked by their docking scores were visually inspected 26 compounds were selected and screened for biological activityusing an HSV reporter virus. One good hit was identified; and using it as a scaffold for the development of novel inhibitors of gB protein fusion, we have undertaken the synthesis of newer compounds for testing. Successful identification of fusion inhibitors could lead to drug candidates that inhibit this conserved fusion protein and clarify how this fusion protein functions, potentially providing new tools to study the prefusion conformationof gB. 67 Poster #21 Is it actually worth calculating binding affinity? Carsten Detering BioSolveIT Inc., Bellevue WA 98008 Predicting binding affinity (aka scoring a protein‐ligand complex) has been heavily criticized as long as it exists. We are introducing a radically new way of looking at calculating binding affinity by taking into account hydrogen bonding and the hydrophobic effect (Hyde), exclusively, and by that measure incorporating the enthalpic and entropic contributions, respectively. Missing interactions are penalized, and most importantly, the method is based on pure physicochemical principles, so can be applied to all sorts of interactions. There are cases, however where there is hardly coincidence between the experimental and the calculated affinity. Does this mean the approach does not work as reliably as we expect? We will look at some examples and check how much we can trust this new method. 68 Poster #22 Making the chemical universe more accessible: de novo design 2.0 Carsten Detering et al. BioSolveIT Inc., Bellevue WA 98008 De novo design has always been tricky in that new compounds were inherently difficult to make. We have come around this problem by including the chemical reactions into a searchable virtual chemistry space: 58 robust chemical reactions (Hartenfeller et al., 2011), 42 from a previous fragment space and 21 text book chemistry reactions were collated and together with building blocks from trusted vendors, and therefore a virtual chemistry space generated, containing 16.314.207.184.647.693 molecules (more than 16 quadrillion compounds!). All these virtual molecules contain high likelihood of straight forward synthetic access. Together with this literature‐derived collection of compounds we provide a unique search method that is capable of handling such vast amounts of molecules relatively easily. Imagine de novo design of (a) hit expansion libraries, (b) follow‐up series and (c) fragment evolution design from within an all accessible, gigantic compound space. We will introduce the building of the space as well as the search method Acknowledgments: Christian Lemmen, Markus Lilienthal, BioSolveIT GmbH References: Hartenfeller et al. (2011), “A Collection of Robust Organic Synthesis Reactions for In Silico Molecule Design”, J. Chem. Inf. Model. 2011, 51, 3093–3098 69 Poster #23 Tumour selective delivery of poly(ADP‐ribose)polymerase‐1 (PARP1) inhibitors Benjamin D. Dickson, Way Wua Wong, William R. Wilson, Michael P. Hay Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, New Zealand [email protected] The recent registration of olaparib for ovarian cancer patients with defects in homologous recombination repair (e.g. BRCA mutations) signalled the culmination of decades of work to develop PARP1 inhibitors. One concern, however, is potentiation of normal tissue toxicity when PARP1 inhibitors are used in combination with DNA damaging agents (e.g. radiation therapy). Hypoxia is present in a wide range of tumours and provides an “address” for tumour‐selective drug delivery. We describe our preliminary work to identify effective hypoxia‐activated prodrugs (HAPs) of olaparib and related PARP1 inhibitors. A prodrug of this type contains the core inhibitor with a “trigger” moiety installed at an appropriate site to prevent PARP1 inhibition. The “trigger” is a bioreducible subunit (e.g. nitroimidazolyl‐) that is stable in normoxic tissues, but is enzymatically reduced in hypoxic tissues and fragments rapidly yielding the active PARP1 inhibitor. We report on various trigger‐inhibitor combinations and their potential as HAPs. Figure 1. Deactivation of a PARP1 inhibitor via addition of a bioreducible trigger. 70 Poster #24 Addressing Challenges of Low Clearance in Drug Discovery Li Di, Karen Atkinson, Xin Yan Pfizer Inc. [email protected] Discovering and developing drugs with low clearance is often the goal of drug discovery teams in order to enhance exposure, reduce dose and prolong half‐life. However, low clearance presents a great challenge for DMPK scientists to project dose and dosing frequency, predict drug‐drug interaction potential and anticipate circulating metabolites. There are no methods available in drug discovery to address low clearance challenges until recently. The novel hepatocyte relay assay enables high‐confident prediction of clearance and dose, identification of metabolites and reaction phenotyping for low clearance compounds. This poster will highlight the applications of the novel assay to enable drug discovery and development portfolios. 71 Poster #25 Lipophilic Isosteres of a π‐π Stacking Interaction: New Inhibitors of Bcl‐2‐Bak Interactions Michäel Doré, B. Barry Touré, Naeem Yusuff, Carol Joud, Kara Herlihy, Michael Visser, Clayton Springer, Xiaoling Xie, Dale Porter Novartis Institutes for BioMedical Research Inc., Global Discovery Chemistry, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States Overexpression of the antiapoptotic members of the Bcl‐2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. The discovery of new Bcl‐2 protein–protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π–π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X‐ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies. 72 Poster #26 Evaluation of [18F]‐RAGER: a small molecule PET ligand for the Receptor for Advanced Glycation Endproducts Lindsey Drake, Brian Carey, Allen Brooks, Maria Fawaz, Allie Sowa, Megan Stewart, Carole Quesada, and Peter J. H Scott University of Michigan The receptor for advanced glycation endproducts (RAGE) is a cell surface receptor implicated in the inflammation pathway and is known to have a variety of ligands: insulin, amyloid‐β (Aβ), S100, etc. RAGE has been identified as a mediator of Aβ influx and could be an early indicator of Alzheimer’s disease. PET radiotracers that can be used to quantify CNS RAGE will aid in elucidating the complexity of this receptor. We previously reported the initial synthesis and evaluation of [18F]‐RAGER, a small molecule ligand for RAGE (KD= 15 nM), which showed CNS penetration and increased uptake in areas of the brain known to
express RAGE. However, metabolic stability using rat liver microsomes indicated a very short half‐life (less than 5 minutes). Further metabolic studies using primate microsomes and competitive imaging studies in primates will be reported. Additionally, analogues of RAGER are being developed to increase metabolic stability while maintaining specificity. 73 Poster #27 Development of MK‐8719, a Novel Inhibitor of OGA for the Treatment of Tauopathies, Utilizing [18F]MK‐8553 as a Target‐Selective PET Tracer Joseph L. Duffy*1, Harold G. Selnick1, Fred J. Hess1, Lili Zhang1, Xiaohai Wang1, David Vocadlo2, Ernest McEachern2, Yuanxi Zhou2, Wenping Li1, Eric Hostetler1, Cristian Salinas1, Talakad Lohith1, Kerry Riffel1, Jeff Evelhoch1, Thomas McAvoy1, Jacob Marcus1, Dawn Toolan1, Ruben DeClercq3, Koen Van Laere4, Kim Serdons4, Guy Bormans4, Jan de Hoon4, Sean M. Smith1, Arie Struyk1, John J. Renger1, Mark S. Forman1, Darryle D. Schoepp1 Merck and Co., Inc., Kenilworth, NJ, USA; 2Alectos Therapeutics Inc., Burnaby, BC, Canada; 3MSD (Europe), Brussels, Belgium; 4Universitaire Ziekenhuizen and Katholieke Universiteit, Leuven, Belgium [email protected] 1
The O‐GlcNAcase (OGA) enzyme mediates the removal of post‐translational O‐linked N‐
acetylglucosamine (O‐GlcNAc) substituents from serine and threonine residues of intracellular proteins. Preclinical studies in transgenic (Tg4510) mice demonstrate that selective inhibition of OGA increases brain protein O‐GlcNAcylation and decreases tau protein aggregation that is associated with many neurodegenerative disorders including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). MK‐8719 is a potent and selective small molecule OGA inhibitor that is being developed for the treatment of PSP. This presentation will review the preclinical profile of MK‐8719, including the in vivo inhibition of neurofibrillary tangle formation, attenuation of neurodegeneration, and attenuation of forebrain volume loss by vMRI in Tg4510 mice. Concurrently, [18F]MK‐8553 was developed as a potent and selective OGA positron emission tomography (PET) target engagement tool. Clinical PK / PD for MK‐8719 and clinical PET displacement data of [18F]MK‐
8553 in healthy volunteers will be disclosed. 74 Poster #28 Discovery of a Novel Series of Aminoquinoline Glucagon Receptor Antagonists David C. Ebner*; Esther C. Y. Lee, Kevin J. Filipski, Matthew F. Sammons, Benjamin D. Stevens, Meihua Tu, Mary T. Didiuk, John Litchfield, Janice Brown, Jeffrey A. Pfefferkorn, Angel Guzman‐Perez Pfizer Worldwide Research and Development, Cambridge, MA, USA The glucagon receptor, a class B G‐protein coupled receptor, promotes gluconeogenesis and glycogenolysis in the liver when stimulated by glucagon. In type II diabetes, elevated glucagon levels lead to increased hepatic glucose output, contributing to hyperglycemia. Glucagon receptor antagonism has the potential to reduce hepatic glucose output and treat diabetes. While a variety of antagonists have been reported, many of these chemotypes suffer from poor physicochemical properties. We developed a novel series of low molecular weight 2‐
aminoquinoline glucagon receptor antagonists with reduced lipophilicity. Optimization of this series involved overcoming several synthetic challenges. As a result, we identified a lead with good in vitro metabolic and safety profiles, oral bioavailability, and an acceptable in vivo half‐
life in rats and dogs, demonstrating the potential of this series for the treatment of diabetes. 75 Poster #29 Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone‐based sulfonamide derivatives Fadi M. Awadallah,a Tamer A. El‐Waei,a Mona M. Hanna,a Safinaz E. Abbas,a Mariangela Ceruso,b Beyza Ecem Oz,b,c Ozen Ozensoy Guler,b,c Claudiu T. Supuranb a
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El‐
Eini Street, 11562,Cairo Egypt; bUniversity of Florence, Neurofarba Department, Via Ugo Schiff 6, Polo Scientifico, 50019, Sesto Fiorentino (Firenze) Italy; cYildirim Beyazit University Faculty of Medicine Department of Medical Biology, Cinnah Campus, Ankara, Turkey Four series of sulfonamides incorporating chromone moieties were synthesized and assessed for their cytotoxic activity against MCF‐7 and A‐549 cell lines, considering the fact that some of these tumors overexpress isoforms of carbonic anhydrase (CA, EC 4.2.1.1) which is inhibited by sulfonamides. Most new sulfonamides showed weak inhibitory activity against the off‐target, cytosolic isoforms hCA I, II but effectively inhibited the tumor‐associated hCA IX and XII. The most active compounds featured a primary SO2NH2 group and were active in the low micromolar range against MCF‐7 and A‐549 cell lines. Compound 4a showed IC50 of 0.72 and 0.50 μM against MCF‐7 and A‐ 549 cell lines, respectively, and was further evaluated for its apoptotic activity which proved enhanced in both tumor types. Compound 4a (general formula B; R=H) has IC50 of 0.72 and 0.50 μM against MCF‐7 and A‐549 cells, respectively. It has Ki of 29.75 and 4.54 nM on hCA IX and XII, respectively. It induces a significant elevation of P‐53and BAX genes expression with concurrent reduction in the expression of the anti‐apoptotic Bcl‐2 gene. It causes a significant cell cycle arrest at Go/G1 phase and at S phase in MCF‐7 and A‐549 cells, respectively. It raises the % of early apoptotic cells to 94.12 and 74.77% in breast and lung cells, respectively. 76 Poster #30 Investigation of Effect of N‐Substituents on Delta Opioid Receptor Inverse Agonism Hideaki Fujii,a,b Eika Higashi,a Shigeto Hirayama,a Minami Nakamura,c Takashi Iwai,c Kennosuke Itoh,a Toru Nemoto,a and Mitsuo Tanabeb,c Department of Medicinal Chemistry, School of Pharmacy, Kitasato University; b
Medicinal Research Laboratories, School of Pharmacy, Kitasato University; cDepartment of Pharmacology, School of Pharmacy, Kitasato University [email protected]‐u.ac.jp a
We have already reported that compound with 2,2,2‐trifluoroethyl group on the 17‐nitrogen of the selective DOR (delta opioid receptor) antagonist NTI exhibited inverse agonist activities for the DOR. Therefore, we focused on the electron‐withdrawing property of fluorine atoms and synthesized compounds with a variety of electron‐withdrawing substituents on the 17‐nitrogen to examine the effect on the inverse agonist activities. Surprisingly, 17‐cyclopropanecarbonyl derivatives (amide type compounds), which lack the basic nitrogen believed to be an important pharmacophore to interact with the opioid receptors, showed potent DOR inverse agonist activities. Among the tested compounds the most potent DOR inverse agonist was evaluated using mice memory deficit model under restraint stress to induce the reversing effect of the memory deficit, which was blocked by NTI. We will present the syntheses, opioid receptor binding assays, [35S]GTPS binding assays, and in vivo evaluation of these derivatives for details. 77 Poster #31 Modulating the eIF4E‐4E‐BP Protein‐Protein Interaction in Cancer Erin Gallagher, Arya Menon, Lauren Mishra, Amanda L. Garner University of Michigan [email protected] Dysregulation of the mTORC1 pathway is implicated in cancer, but attempts to target mTORC1 directly have been largely unsuccessful due to drug resistance. Resistance mostly results from dysregulation of cap‐dependent translation, of which eIF4E is the rate‐limiting factor. eIF4E is elevated in approximately 30% of cancers, its overexpression correlates with poor prognosis, and it induces expression of proliferation and survival proteins. Its activity is regulated by the 4E‐BPs via an inhibitory protein‐protein interaction (PPI) which prevents formation of the eIF4F translation‐initiation complex and cap‐dependent translation. This PPI therefore presents itself as a target in treating cancer. We synthesized 4E‐BP1 based stapled‐peptides to modulate this PPI. In MBA‐MD‐231 cell‐based assays, low micromolar concentrations show the ability to inhibit eIF4E’s PPI with the eIF4F complex, decrease expression of c‐Myc, and inhibit colony formation. These stapled‐peptides therefore have the potential to act as probes to validate the eIF4E‐4E‐BP1 PPI as a cancer target. 78 Poster #32 Development of novel positive allosteric modulators for the mGlu1 receptor: improving the pharmacokinetic profile of lead series VU0486321 Pedro M. Garcia‐Barrantesa, Hyekyung P. Choa,b, Anna L. Blobauma, Colleen M. Niswendera,b, P. Jeffrey Conna,b, Craig W. Lindsleya,b,c a
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; bDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; cDepartment of Chemistry, Vanderbilt University, Nashville, TN 37232, USA [email protected] Schizophrenia is a highly prevalent neuropsychiatric disorder and a public health challenge due to its severity and early onset. Current available therapies alleviate positive symptoms, but not symptoms in other domains of the disease. Encoded by the GRM1 gene, the mGlu1 receptor is a Gq‐protein couple receptor that acts by modulating calcium currents, favoring the activation of the NMDA receptor. Recent genetic studies showed that mutations in the GRM1 gene are enriched in schizophrenic and bipolar patients, and we confirmed that a subset of these mutations decreased the response of the receptor; indicating that therapies targeting the receptor’s activation might be beneficial in schizophrenic patients. In this work, we present efforts towards the optimization of novel mGlu1 positive allosteric modulators that lead to the discovery of VU6004909 and VU0487351; potent and selective compounds, with good CNS penetration and a balanced DMPK profile. 79 Poster #33 Design and Synthesis of Small Molecule Inhibitors for β‐Catenin/T‐Cell Factor Protein—
Protein Interactions Wenxing Guo, Haitao (Mark) Ji Department of Chemistry, University of Utah The Wnt signaling pathways are signal transduction pathways that play a pivotal role in cell functions. However, mutations of components in the pathway can lead to aberrant activation thus resulting in the formation of cancers such as colorectal cancer. Studies have shown that the overactivation is dependent on the formation of the β‐catenin/T‐cell factor (Tcf) complex in the cell nucleus. Thus, targeting and disrupting this complex is an appealing approach in cancer therapy. This research focuses on the structure‐based design and synthesis of small molecule inhibitors, which can disrupt the β‐catenin/Tcf complex. The Tcf G13ANDE17 (Fig. 1a) is binding in a deep cleft of β‐catenin. Using bioisosteric replacement, crucial elements of Tcf will be mimicked. Starting with a simple benzoic acid derivative with high micromolar binding affinity, the molecule is gradually evolved into a more complex molecule with additional functional groups to gain more interactions. Consequently inhibitors with low micromolar or nanomolar binding affinities can be obtained. Furthermore, site directed mutagenesis studies shows that the potent inhibitor binds to the desired region of β‐catenin. Fig. 1a Human Tcf4 binding to β‐catenin. 1b This work sets the foundation to further improve the Fragment evolution approach. binding affinity of the inhibitor. SAR and cell based assay results will be presented. R
b
O
O
OH
O
HO
O
H
N
O
Glu 17
N
H
HO
H
N
N
R
N
X
O
OH
Asp 16
N
N
HN N
Ki 100 mM
N
N
Ki 0.9 mM
N N
H
80 Poster #34 Effect of resveratrol on sarcoplasmic reticulum Ca2+‐ATPase 2 gene expression in in cardiomyocytes subjected to oxidative stress Abigail Guzmán‐Bárcenas1, Gabriela Rodríguez‐Rodríguez1, Ángel Zarain‐Herzberg1* 1
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México. Av Universidad #3000, C.U., México, D.F., C.P. 04510 [email protected] Resveratrol (RSV) is a polyphenol that activates SIRT1 and protects the heart against oxidative stress by regulating synthesis of antioxidants and down‐regulating free radicals. RSV increases the expression of sarcoplasmic reticulum Ca2+‐ATPase‐2 (SERCA2) preserving cardiac function in diabetic mice, suggesting that SIRT1 could function as a transcriptional activator of SERCA2 gene. The aim of this work is to examine the effect of RSV on SERCA2a expression in primary cultures of neonatal rat cardiomyocytes under oxidative stress induced by H2O2. We found that treatment with 150 μM RSV for 72 hours increases mRNA abundance of SERCA2a and SIRT1 (1.5‐fold), BIM and Bcl‐2 (1.6‐fold), catalase (2.3‐fold) and SOD1 (1.8‐fold). Cardiomyocytes pre‐
treated with RSV showed that oxidative stress induced by H2O2 prevents the decrease in mRNA level of SERCA2a, SOD1, CAT, Bcl‐2, and also prevents cellular viability loss, suggesting that RSV protects cardiomyocytes from oxidative stress damage. Funded by CONACyT grant 164413. 81 Poster #35 Chemical control of cullin neddylation through inhibition of the DCN1‐UBC12 interaction Hammill, J. T.1,*; Scott, D. C.2,3,*; Min, J.1; Connelly, M.1; Bhasin, D.1; Huang, G.4; Barrios, R.1; Sviderskiy, V.3; Bharatham, K.1; Attia, R. N.1; Holbrook, G.1; Zhu, F.1; Matheny, A.1; Yang, L.1; Low, J.1; Ong, S. S.1; Chen, Y.1; Evison, B.1; Chen, T.1; Shelat, A.1; Harper, J. W.5; Singh, B.4; Schulman, B. A.2,3; Guy, R. K.1 1
Department of Chemical Biology and Theraputics, St. Jude Children’s Research Hospital, Memphis, Tennessee, 38105 USA; 2Howard Hughes Medical Institute, St. Jude Children’s Research Hospital, Memphis, Tennessee, 38105 USA; 3Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, 38105 USA; 4Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York, 10065 USA; 5Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115 USA (*These authors contributed equally) [email protected] Ubiquitin (UB) and ubiquitin‐like protein (UBL) modification pathways have emerged as important targets for oncology drug discovery based on the successes of proteasome inhibitors (e.g. bortezomib or carfelzomib), E3 inhibitors, and the NEDD8 E1 inhibitor MLN4924. The goal of our research program is to develop and characterize small molecule inhibitors of a distinctive UBL ligation pathway involving DCN1. DCN1 was discovered due to its frequent chromosomal amplification and association with poor prognosis in a number of human cancers. To date, we have conducted a high‐throughput screen of 600,000 compounds, identified and validated three unique chemical series for optimization, and used structure‐based optimization of one series to yield a 100‐fold increase in potency as well as improved metabolic stability. We will present the most up to date results from our efforts to understand the consequences of acute pharmacologic inhibition of DCN1 in both cellular and in vivo models. 82 Poster #36 Design, biological activity and ADME properties of pyrrolopyrimidine‐based EGFR‐TK inhibitors Jin Han, Eirik Sundby, Bård Helge Hoff Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, 7491 Trondheim, Norway. [email protected] The epidermal growth factor receptor (EGFR/HER1) and other epidermal growth factor receptors (HER´s) are often amplified, overexpressed or mutated in solid tumors.1‐4 Several low molecular weight organic compounds as Erlotinib and Gefitinib have been found to regulate tyrosine kinases activity, and therefore the epidermal growth factor receptor is an important target in molecular cancer therapy.5,6 A new synthetic route utilizing SEM‐protected 7H‐pyrrolo[2,3‐d]pyrimidine has been established, allowed for an elaborate investigation of delicate 6‐aryl substitution patterns in Suzuki coupling reactions. By perform an extended SAR study and a step‐wise combination of favorable substitution pattern based on our previously knowledge,7‐8 several highly potent pyrrolopyrimidine EGFR‐TK inhibitors has recently been identified. Sixteen of these compounds were found more active than the commercial drug Erlotinib in enzymatic IC50 assay. Selected derivatives were further evaluated for their ADME profile, which revealed increased drug efflux for compounds with activity inducing polar functionalities. Metabolic stability, evaluated by human liver microsomes, revealed half‐life of most of these drug candidates to be better than the reference Erlotinib. This study confirmed these pyrrolopyrimidines as attractive drug candidates and lead structures for further in vivo studies.9 [1] N.E. Hynes, G. MacDonald, Curr.Opin.Cell.Biol., 2009, 21, 177‐184. [2] T. Soonthornthum, H. Arias‐Pulido, N. Joste, L. Lomo, C. Muller, T. Rutledge, C. Verschraegen, Ann. Oncol., 2011, 22, 2166‐2178. [3] J.Z. Sun, Y. Lu, Y. Xu, F. Liu, F.Q. Li, Q.L. Wang, C.T. Wu, X.W. Hu, H.F. Duan, Hematol.Oncol., 2012, 30, 89‐97. [4] Y. Yarden, G. Pines, Nat. Rev. Cancer, 2012, 12, 553‐563. [5] Carmi, C.; Mor, M.; Petronini, P. G.; Al_eri, R. R. Biochem. Pharmacol., 2012, 84, 1388‐1399. [6] Dar, A. C. and Shokat, K. M. Annu.Rev.Biochem., 2011, 80, 769‐795. [7] Kaspersen, S. J., Han, J., Nørsett, K. G., Rydså, L., Kjøbli, L., Bugge, S., Bjørkøy, G., Sundby, E., Hoff, B. H., Eur. J. Pharm. Sci., 2014, 59, 69‐82 [8] Sundby, E., Han, J.,Kaspersen, S. J., Hoff, B. H., Eur. J. Pharm. Sci., 2015, 80, 56‐65 [9] Han, J. et al, manuscript in preparation 83 Poster #37 Discovery of Small Molecule Enzyme Inhibitors of E. Coli IspD 1
2
Brian E. Hartnett , Chi‐Hao Luan , James R. Horn1 and Timothy J. Hagen1 1
Department of Chemistry and Biochemistry Northern Illinois University DeKalb, IL 60115; High Throughput Analysis Laboratory, Northwestern University, Evanston, IL 60208 [email protected] 2
Antimicrobial resistance is rising at an alarming rate. The non‐mevalonate (MEP) pathway is an attractive target to discover new anti‐infective agents, due to the fact that it is found in eubacteria and plants, and not within mammals. In the current study, we examined the biophysical properties and enzyme inhibition of Escherichia coli 2‐C‐methyl‐D‐erythritol 4‐
phosphate cytidylyltransferase (EcIspD) to discover novel inhibitors. Currently, there are very few known inhibitors of EcIspD, with the majority possessing weak potency (IC values in the millimolar range). High throughput thermal shift screening of the MicroSource Spectrum library against EcIspD revealed several potential hits that were subsequently investigated using a plate‐based enzymatic assay. Results from the enzymatic assays revealed a small set of compounds possessing high micromolar inhibition. The hit compounds could be used for future development of more potent EcIspD inhibitors. 84 Poster #38 Investigation of 2‐methylpyrrole compounds as BET bromodomain inhibitors for the treatment of cancer Lisa A. Hasvold, Dachun Liu, John Pratt, George S. Sheppard, Yu Shen, Xiaoyu Lin, Xiaoli Huang, Scott Warder, Denise Wilcox, Leiming Li, Velitchka Bontcheva, F. Greg Buchanan, Chang H. Park, Andrew Petros, Chaohong Sun, Peter Kovar, Nirupama B. Soni, Steven Elmore, Warren Kati, Keith McDaniel Oncology Discovery, Global Pharmaceutical Research & Development, AbbVie, North Chicago, IL 60064 [email protected] Phenotypic cell‐based screening assays combined with affinity chromatography and mass‐
spectrometry identified the BET family of bromodomains as potential targets for blocking proliferation in a variety of cancer cell lines. Proteins containing bromodomains act as epigenetic readers that recognize acetylated lysines of histones and recruit transcription factors to chromatin. Many of the interacting transcription factors and their target genes are known to play roles in the pathogenesis of cancer. Fragment 1 was identified from the screening of an 18000 member fragment library in a 2‐dimensional NMR binding assay utilizing a 13C‐labeled 2nd bromodomain of BRD4. Medicinal chemistry supported by X‐ray structure‐based design provided analogs (2) with improved binding affinities and led to the design of bicyclic 2‐
methylpyrrole cores (3) with further enhanced potency. An advanced bicyclic analog exhibited oral bioavailability in rodent PK studies and demonstrated significant tumor growth inhibition in mouse xenograft models. 85 Poster #39 Discovery and SAR development of pyridone and pyridazinone bromodomain inhibitors John K. Pratt, Le Wang, George S. Sheppard, Dachun Liu, Xiaoyu Lin, Xiaoli Huang, Denise Wilcox, Yu Shen, Chang Park, Andrew Petros, Peter Kovar, Daniel Albert, Terry Magoc, Warren Kati, Keith McDaniel Oncology Discovery, Research & Development, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064 [email protected] Reversible lysine acetylation plays a central role for regulating the transcription of genes. Acetylated lysines are recognized by conserved protein modules known as bromodomains. Members of the BET family of bromodomain containing proteins were identified as potential targets for blocking proliferation in a variety of cancer cell lines. A 2‐dimensional NMR binding assay utilizing the 2nd bromodomain of BRD4 was used to screen a fragment library (MW ≤ 225). The assay identified a diverse set of heterocyclic fragments with weak binding affinities, including a phenyl pyridazinone (1, Kd = 130 uM). Traditional SAR investigation of fragment 1, aided by X‐ray structure based design, enabled the synthesis of pyridone based inhibitors (2) with single digit nanomolar binding affinities against the BRD4 tandem binding domain. Advanced analogs in the pyridone inhibitor series exhibited high oral bioavailability in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models. 86 Poster #40 Discovery and SAR of novel pyrrolopyridones as BET inhibitors Dachun Liu, Le Wang, John Pratt, Lisa Hasvold, Robert Mantei, George Sheppard, Steve Fidanze, Chang Park, Yu Shen, Xiaoyu Lin, Mai Bui, Xiaoli Huang, Denise Wilcox, Peter Kovar, Daniel Albert, Terry Magoc, Warren Kati, Keith McDaniel Oncology Discovery, Research & Development, AbbVie Inc., 1 North Waukegan Rd., North Chicago, IL 60064 [email protected] Reversible lysine acetylation plays a central role in regulating gene transcription. Acetylated lysines are recognized by conserved protein structural folds known as bromodomains. The BET family is a subset of related bromodomain‐containing proteins that includes BRD2, BRD3, BRD4, and BRDT. The inhibition of the BET family of bromodomains has been proposed as a therapeutic strategy in oncology. Investigation of BET inhibitors towards oncology indications identified a novel series of pyrrolopyridones. SAR and structure based design led to inhibitors (1) with single digit nanomolar binding potency against the BRD4 BDl/BDll tandem domain. Further optimization of this chemical series through rotationally constricted analogs (2) substantially improved biochemical binding potency and cellular antiproliferative activity. Advanced analogs from these investigations exhibited good rodent PK and tumor growth inhibition in a mouse flank xenograft model. 87 Poster #41 Novel, Covalent Inhibitors of EGFR: Identification of Aminopyrazine Benzimidazoles that Selectively Target Mutant Forms of the Receptor Edward J. Hennessy,*,† Claudio Chuaqui,† Susan Ashton,‡ Nicola Colclough,‡ Darren A. E. Cross,‡ Judit É. Debreczeni,‡ Cath Eberlein,‡ Lakshmaiah Gingipalli,† Teresa C. M. Klinowska,‡ Jonathan P. Orme,‡ Li Sha,† and Xiaoyun Wu† †
Oncology iMed, Innovative Medicines & Early Development, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States; ‡Oncology iMed & Discovery Sciences, Innovative Medicines & Early Development, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom [email protected] Covalent kinase inhibitors have garnered significant interest in recent years, and the approval of Tagrisso (AZD9291/osimertinib) for treatment of EGFR T790M non‐small cell lung cancer is further evidence of the therapeutic potential of such compounds. We will present on a novel series of covalent inhibitors of this target, discovered through a combination of subset screening and structure‐based design. These compounds preferentially inhibit mutant forms of EGFR (activating‐mutant and T790M mutant) over wild‐type EGFR in cellular assays measuring EGFR autophosphorylation and proliferation, suggesting an improved therapeutic index in non‐
small cell lung cancer patients would be achievable relative to established EGFR inhibitors. We will describe our design approaches resulting in the identification of the lead compound 5, and our efforts to develop an understanding of the structure‐activity relationships within this series. In addition, strategies to overcome challenges around metabolic stability and aqueous solubility will be presented. Despite limitations in its physical properties, 5 is orally bioavailable in mice and demonstrates pronounced antitumor activity in in vivo models of mutant EGFR‐driven cancers. 88 Poster #42 Development of Novel μ‐/δ‐Opioid Receptor Analgesics with Reduced Tolerance and Dependence A. Nastase,† S. Henry,† A. Harland,† A. Bender,† N. Griggs,‡ J. Anand,‡ J. Traynor,‡ E. Jutkiewicz,‡ H. Mosberg† †
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; ‡Department of Pharmacology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States Opioid analgesics are among the most widely prescribed and highest‐selling classes of drugs in the pharmaceutical industry, yet their use is accompanied by undesired side effects including tolerance, dependence, and constipation. One strategy to combat these negative side effects while maintaining antinociceptive activity is to activate the μ‐opioid receptor (MOR) while blocking the δ‐opioid receptor (DOR). Our lab has developed a library of peptidomimetic ligands, based on the enkephalin analog JOM13, that display a bifunctional MOR agonist/DOR antagonist profile, capable of eliciting antinociception in vivo without inducing tolerance or dependence. Ongoing research is aimed at identifying key structural features governing potency, efficacy, selectivity, and bioavailability of these ligands. Progress toward these goals will be described. JOM13 Peptidomimetic Lead Overlay 89 Poster #43 Development of 1H‐Pyrazolo[3,4‐b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Matthew D. Hill*, Haiquan Fang, Jeffrey M. Brown, Thaddeus Molski, Amy Easton, Xiaojun Han, Regina Miller, Melissa Hill‐Drzewi, Lizbeth Gallagher, Michele Matchett, Michael Gulianello, Anand Balakrishnan, Robert L. Bertekap, Kenneth S. Santone, Valerie J. Whiterock, Arun Senapati, Siva Digavalli, Xiaoliang Zhuo, Joanne J. Bronson, John E. Macor, and Andrew P. Degnan Bristol‐Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492‐7660, USA [email protected] The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia. We describe a facile and multicomponent synthesis of 1H‐pyrazolo[3,4‐
b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs). Importantly, this chemotype lacked inherent agonist activity and contain neither the aryl‐acetylene‐aryl nor aryl‐
methyleneoxy‐aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of this series do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in non‐MPEP site PAMs that demonstrated activity in two in vivo models. 90 Poster #44 Synthesis and Biological Evaluation of HK‐2 Inhibitor Imelda Hot, Veronique Nogueira, Nissim Hay, and Duncan J. Wardrop Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago 900 South Ashland Avenue, Chicago, IL 60607 Glycolysis is one of the major metabolic pathways and gives rise to intermediates necessary for cell growth and proliferation. The first step of the glycolytic pathway, the conversion of glucose to glucose‐6‐phosphate with concomitant de‐phosphorylation of ATP, is catalyzed by the enzyme hexokinase‐2 (HK‐2). Not only is HK II overexpressed in a large number of cancers, being a major component in supporting malignant cell grow, it is also suppresses the apoptosis of cancer cells. For these reason, targeting this key enzyme with small‐molecule inhibitors is an appealing strategy for the development of novel therapies for the treatment of cancer. The focus of our work is to develop a potent HK‐2 inhibitor and evaluate its effect upon glycolysis in tumor cells. Details of the synthesis of a potential HK‐2 inhibitor are reported along with their biological evaluation. 91 Poster #45 Development of Cancer Stem Cell Depleting ALDH1A Selective Inhibitors as Potential Therapeutics for Ovarian Cancer Brandt C. Huddlea, Cameron D. Buchmanb, Kun Yangc, Mikhail Chtcherbinineb, Ronald J. Buckanovichc, Thomas D. Hurleyb, Scott D. Larsena,1 a
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109; bDivision of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; cDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; 1To whom correspondence should be addressed. [email protected] The presence of a subpopulation of cancer stem‐like cells (CSCs) expressing the surface glycoprotein CD133 and the enzyme Aldehyde Dehydrogenase (ALDH) within ovarian tumors has been associated with poorer cancer patient outcomes. ALDH+ cells show resistance to cisplatin, and engraftment of fewer than 500 CD133+/ALDH+ patient tumor cells is sufficient to establish tumors in mice, implicating these CSCs in recurrence metastasis following treatment in ovarian cancer. Administration of ALDH inhibitors can selectively deplete CD133+ cells and may represent a mechanistically novel treatment for ovarian cancer. While most evidence suggests ALDH1A1 is most critical for CSC function, the ideal selectivity profile among the 19 ALDH isoforms remains unclear. We have generated a library of analogs based on the ALDH1A1 inhibitor A39. Small structural changes have led to substantial improvements in 1A1 potency, widely varying selectivity profiles among the ALDH1A family, and several compounds capable of depleting CSCs in our cellular assay. 92 Poster #46 Identification of GNE‐131: A potent and selective hNaV1.7 inhibitor for the treatment of pain Brian Safina1, Girish Bankar2, Paul Bichler2, Christine Chabot1, Elaine Chang2, Jae Chang1, Chien‐An Chen , Sultan Chowdhury2, Charles Cohen2, Shannon Decker2, Christoph Dehnhardt2, Thilo Focken2, Mike Grimwood2, David Hackos1, Ivan Hemeon2, Kuldip Khakh2, Christopher Koth1, Rainbow Kwan2, Sophia Lin2, Karen Nelkenbrecher2, Daniel Ortwine1, Jodie Pang1, Jian Payandeh1, Lee Robinette2, Tao Sheng2, Shaoyi Sun2, Matt Waldbrook2, Andy White3, Michael Wilson2, Clark Xie2, Clint Young2, Alla Zenova2, Yi Zhang3, Fred Hu3, Dan Sutherlin1 1
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States; 2Xenon Pharmaceuticals Inc., 200–3650 Gilmore Way, Burnaby, BC,V5G 4W8, Canada; 3
ChemPartner Inc., Building No 5, 998 Halei Rd, Zhangjiang Hi‐Tech Park, Pudong New Area, Shanghai [email protected], [email protected], [email protected] In an effort to identify potent, orally available, and selective Nav1.7 inhibitors with reasonable metabolic stability, GNE‐131 was identified. The discovery of this compound was initiated through the optimization of acyl sulfonamide, CmpdA that had good potency on the channel but poor metabolic stability. Through our exploration of the acylsulfonamide pharmacophore we investigated conformationally constricted isosteres of the acidic head group and identified several active 6‐5 ring systems. Further optimization of potency and physicochemical properties resulted in GNE‐131. GNE‐131 showed improved lipophilic ligand efficiency (LLE) and better metabolic stability. It represents a promising potent and selective inhibitor of hNaV1.7 for the treatment of pain. 93 Poster #47 Evaluation of 2‐aminobenzothiazoles (BET) as potent inhibitors of Mycobacterium tuberculosis Jo‐Ann Jee1*, Shilah Bonnett1, Joshua Odingo1, Tanya Parish1 1
Infectious Disease Research Institute, 1616 Eastlake Avenue E, Seattle, WA 98102, USA *jo‐[email protected] The search for new drugs to treat tuberculosis is critical. We used a targeted whole cell screen approach and we identified a series of 2‐aminobenzothiazoles (BET) that exhibits good activity against Mycobacterium tuberculosis. Our screen enables us to find compounds that target the secretory pathway, in particular the essential signal peptidase LepB. LepB is an attractive drug target as it has a catalytic domain that is accessible within the cell to inhibitors, and is selective due to a bacteria‐specific catalytic dyad mechanism. We synthesized analogs in the BET series and determined in vitro activity against M. tuberculosis to understand the structure‐activity relationship (SAR). We identified a number of analogs that are potent against M. tuberculosis, and that appear to target LepB and/or the protein secretion pathway. We will present the synthesis and biological evaluation of these BET analogs. 94 Poster #48 Novel synthetic ligands for REV‐ERBα: The role of circadian drug discovery targets in pulmonary inflammation. Understanding the rhythm of pulmonary inflammation. D. Heulyn Jones,a Justyna Wojno,a Stefano Bresciani,a James P. Tellam,a Anthony W. J. Cooper,b Lisa A. Orband‐Miller,c Ryan P. Trump,c William Zuercher,c Timothy M. Willson,c Andrew Loudon,d David Ray,e Stuart N. Farrow,b Nicholas C. O. Tomkinsona a
WestCHEM, Department of Pure & Applied Chemistry, Thomas Graham Building, University of Strathclyde, Glasgow, G1 1XL, U.K. bMolecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Hertfordshire, SG1 2NY, U.K. cMolecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709‐
3398, United States. dFaculty of Life Sciences and eFaculty of Medical and Human Sciences, University of Manchester, Manchester, M13 9PT, U.K. [email protected] Pulmonary inflammation shows strong diurnal variations with high mortality rates and hospital admissions in the early hours of the day. Our “master clock” that controls circadian rhythms is located in the suprachiasmatic nucleus and is now well described. However, the mechanisms behind the circadian oscillation in the lung and other organs remain poorly understood. On the molecular level, nuclear receptors REV‐ERBα and RORα are the negative and positive arms of the circadian clock.1 To date only a few synthetic ligands for REV‐ERBα have been reported. GSK4112 was found to significantly repress IL‐6 secretion in a dose‐dependent manner from lipopolysaccharide (LPS) stimulated human myelo‐monocytic cells. This study suggested that REV‐ERBα mediates circadian pattern of pulmonary inflammation through selective regulation of inflammatory cytokines.2 However, lack of selectivity over LXRα nuclear receptor, which also shows an anti‐
inflammatory effect, could seriously limit therapeutic usefulness of existing probes. Therefore, we designed and synthesised novel REV‐ERBα agonists based on GSK4112 for selectivity, potency and bioavailability. Optimised synthetic REV‐ERBα ligands will be presented highlighting their ability to suppress BMAL and IL‐6 expression from human cells with excellent selectivity over LXRα.3 1. C. H. Ko, J. S. Takahashi Hum. Mol. Genet. 2006, 15, R271–R277. 2. J. E. Gibbs et al. PNAS 2012, 109, 582‐587. 3. R. P. Trump et al. J. Med. Chem. 2013, 56, 4729–4737. 95 Poster #49 Novel rabbit‐derived peptideS as potent analgesics a
Chai‐Lin Kao, Hui‐Ting Chen,b Chen‐Lung Steve Linc,d a Department of Medicinal and Applied Chemistry, b Department of Fragrance and Cosmetic Science, c Graduate School of Medicine, Kaohsiung Medical University, Taiwan d Division of Cellular and Immune Therapy, Department of Medical Research, Kaohsiung Medical University, Taiwan [email protected] An extracted from rabbits skin with inflammation elicited by inoculation of the virus Vaccinia variolae has been used for treatment of pain for decades. Pharmacological experiments and clinical applications showed that this mixture of bioactive agents have potent analgesic effects against all kinds of symptomatic neuralgia, lumbago, cholecystalgia, angina, arterial embolism pains, acute pains from wound, burn and scald, pains in surgery or post‐surgery. However, the active component in the mixture remains puzzle. Herein, we report the identification of active compounds in this mixture and its biological assays. The biological evaluation revealed that a peptide fragment of rabbit α1‐anti‐proteinse F had remarkable analgesic effects in mice with acute visceral pain. The stability test indicated that this peptide remains intact after 7 days of treatment at pH 2 environment. Meanwhile, alanine scanning experiments and optimization lead to more potent analogues. 96 Poster #50 The Discovery of Novel Scaffolds as NR2B Receptor Negative Allosteric Modulators George N. Karageorge, Lorin Thompson, Joanne Bronson, Larry Marcin, Linda Bristow, Michael Sinz, Jyoti Gulia, James Cook and John E. Macor Bristol‐Myers Squibb, R&D, 5 Research Parkway, Wallingford, CT 06492 [email protected] The discovery of the positive effects of ketamine in severely depressed patients has opened up a new avenue for the treatment of depression. Both ketamine and CP‐101,606 have been shown to be effective in alleviating symptoms of depression in severely depressed patients. This treatment is believed to be mediated via modulation of the NR2B receptor on the NMDA (N‐
methyl d‐aspartic acid) receptor complex. Noting this new opportunity for treating depression, we sought novel scaffolds which could provide potent NR2B negative allosteric modulator (NAM) activity as potential novel antidepressants. 97 Poster #51 Design, Synthesis and Screening of Triaminopyrimidine Analogs as Inhibitors of Inflammatory Caspases Caitlin Karver DePaul University Inflammatory caspases, including caspase‐1, ‐4, and ‐5, are involved in the formation and function of the canonical (caspase‐1) and noncanonical (caspase‐4 and ‐5) inflammasomes. Caspase‐1 has been studied as a target for therapeutics for autoinflammatory and autoimmune disorders with little success. Much less has effort been devoted to inhibition of caspases‐4 and ‐
5. Previous research in our group has identified a triaminopyrimidine scaffold whose potency and specificity for caspases varies greatly depending on the identity of the aryl substituent. Discussed here are the design and synthesis of these analogs as well as the in vitro and cellular biochemical assays. We have discovered a handful of molecules that are slightly selective for caspase‐5 over the other inflammatory caspases. Gratifyingly, some of these analogs are also active within the cellular model of inflammation. 98 Poster #52 Inhibitors of the ubiquitin ligase Nedd4‐1 discovered by covalent fragment screening Stefan Kathman, Ingrid Span, Aaron Smith, Ziyang Xu, Jennifer Zhan, Amy Rosenzweig, Alexander Statsyuk Northwestern University, Department of Chemistry, 2145 Sheridan Rd., Evanston, IL 60208 There has been a recent upsurge of interest in cysteine‐reactive covalent inhibitors. However, there are few good methods to discover new cysteine‐reactive inhibitors for enzymes for which reversible binding scaffolds are not already known. To this end, I rationally designed a chemical system to attach a cysteine‐reactive electrophile to 200 drug‐like fragments without significant alterations in the thiol reactivity of the attached electrophile, ensuring that specific binding and not increased reactivity will produce hits. I used this covalent fragment library to discover inhibitors of the HECT E3 ubiquitin ligase Nedd4‐1, an enzyme implicated in viral budding, cancers, and neurodegenerative diseases that has no validated inhibitors. These covalents inhibitor reduce the binding affinity of Nedd4‐1 for ubiquitin, which is necessary for polyubiquitination processivity. Notably, Nedd4‐1 treated with our inhibitor is unable to polyubiquitinate a substrate in the presence of a deubiquitinase. Cell‐based studies of this inhibitor are currently ongoing. 99 Poster #53 Imidazopyridine Inhibitors of Dual Leucine Zipper Kinase (DLK) for Neurodegenerative Indications Terry Kellar,* Snahel Patel, Anthony Estrada, Seth Harris, Paul Gibbons, Malcolm Huestis, Daniel G. M. Shore, Joseph Lyssikatos, Jonathan Cheong, Brian Dean, Gauri Deshmukh, Amy Gustafson, Yichin Liu, Xingrong Liu, Emile Plise, Amy Sambrone, Young Shin, Peter Yin, Joseph Lewcock, Michael Siu Departments of Discovery Chemistry, Neuroscience, Drug Metabolism and Pharmacokinetics, and Biochemical and Cellular Pharmacology,Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States [email protected] Dual Leucine Zipper Kinase (DLK) is an upstream regulator for the c‐Jun N‐terminal kinase (JNK) signaling pathway, which has been linked to neurodegeneration. Disruption of JNK pathway signaling through DLK inhibition may provide neuroprotective effects. Several imidazopyridine‐
based DLK inhibitors, derived from a related purine scaffold, are presented as brain‐penetrant, selective compounds. 100 Poster #54 Blocking Bleach Production with Reversible Inhibitors of Myeloperoxidase Ellen Kick, Scott Shaw, Meriah Valente, Nick Wurtz, Andrew Viet, Andrew Dilger, Benjamin Vokits, Javed Khan, Sutjano Jusuf, Gayani Fernando, Fred Lo, Xiaoquin Liu, Kimberley Nowak, Kristen Pike, Ashok Dongre, Ji Gao, Greg Locke, Lisa Kopcho, Paul Sleph, Michael Basso, Lei Zhao, Ruth Wexler, David Harden, Lynn Abell and Franck Duclos Research and Development, Bristol‐Myers Squibb, 350 Carter Road, Hopewell, NJ 08540 [email protected] Myeloperoxidase (MPO) is a heme peroxidase present in neutrophils and macrophages that produces bleach (HOCl) as part of the innate immune system. While activated neutrophil release of MPO is important to defend against infections, in chronic inflammatory conditions MPO release from macrophages and neutrophils can cause deleterious oxidation of endogenous proteins. For instance, MPO oxidation of apoA1, a protein component in high density lipoproteins, reduces the ability of apoA1 to efflux cholesterol from cells. Due to the high oxidative potential of MPO, most reported inhibitors are either substrates or irreversible inhibitors. An HTS campaign led to the discovery of potent, reversible triazolopyrimidine inhibitors of MPO that were demonstrated to bind to the heme pocket by crystallography. Lead optimization led us to discover potent triazolopyridine inhibitors of MPO that will be described. 101 Poster #55 A Rapid Experimental Polar Surface Area (EPSA) Assay J. P. Kiplinger, P. M. Lefebvre, M. J. Rego, E. S. Rouse Averica Discovery Services, 260 Cedar Hill Street, Marlborough MA 01752 Predictive assays or calculations are established approaches to understanding a drug’s potential bioavailability. A key physical property to understanding this is polar surface area, sometimes discussed as hydrogen bond availability. The most common way of evaluating this is to calculate the structure’s Topological Polar Surface Area (TPSA). While valuable for rank ordering similar molecules, TPSA suffers by not accounting for conformational changes in a molecule in solution. The EPSA (Experimental Polar Surface Area) assay experimentally determines the relative degree of polar interaction. This method assesses polarity by retention time using controlled Supercritical Fluid Chromatography (SFC) conditions in a standardized method. By operating in a less polar solvent system that is conducive to IMHB formation, SFC yields an EPSA measurement that more reliably reproduces data from membrane permeability assays. The assay is straightforward to implement on contemporary analytical scale SFC instrumentation. The poster discusses a simplified implementation of the assay in a high‐throughput environment, and its use in rapid characterization of peptide drug discovery compounds and small molecule therapeutics. 102 Poster #56 Design, synthesis and biological evaluation of N4‐phenylsubstituted‐7H‐pyrrolo[2,3‐
d]pyrimidin‐4‐amines as multi‐targeted anticancer agents targeting EGFR, JAK2 and AURKA Sonali Kurup,1,* Bradley McCallister,1 Robert Senones, 1 Trusha Mistry, 1 Stephen Zych,1 Anthony Fanizzi, 2 Dan Stanford,2 Priya Pancholi,3 Samhita Bapat,3 Tanvi Visal, 3 Vikas Sehdev3 College of Pharmacy, Roosevelt University, Schaumburg, IL United States; 2Harper College, Schaumburg, IL United States; 3Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY United States [email protected] 1
Redundant pathways mediated through janus kinase 2 (JAK2) and aurora kinase A (AURKA) contribute toward the acquisition of resistance to selective epidermal growth factor receptor kinase (EGFR) inhibitors in esophageal, lung, breast and thyroid cancers. Novel small molecules with multi‐targeted inhibitory attributes against EGFR, AURKA and JAK2 could possibly alleviate problems of resistance observed with existing single EGFR inhibitors. Kurup et al. identified compound 1, a 4‐methoxyphenylpyrrolo[2,3‐d]pyrimidin‐4‐amine as a micromolar inhibitor of AURKA and JAK2, and a nanomolar inhibitor of EGFR. Compound 1 demonstrated sub‐
micromolar inhibition of esophageal adenocarcinoma cells. Using compound 1 as the lead, we explored substitutions on the 4‐anilino ring of 1 and evaluated their effect(s) on the specificity and potency of multiple kinase inhibition. The design, synthesis and inhibitory activities of these compounds will be presented and discussed. 103 Poster #57 Discovery of Substituted (4‐phenyl‐1H‐imidazol‐2‐yl)methanamine as Potent Somatostatin Receptor 3 Agonists Zhong Lai,a,1 Shuwen He,a Edward C. Sherer,a Zhicai Wu,a Yang Yu,a Qingmei Hong,a David X. Yang,a Liangqing Guo,a Derun Li,a Quang Tuang,a Gary G. Chicchi,b Dorina Trusca,b Kwei‐Lan Tsao,b Yun‐Ping Zhou,b Andrew D. Howard,b Ravi P. Nargund,a William K. Hagmanna a
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 539, Kenilworth , NJ 07033, USA; bDepartment of Diabetes Research, Merck Research Laboratories, PO Box 539, Kenilworth, NJ 07033, USA We report SAR studies on a novel non‐peptidic Somatostatin Receptor 3 (SSTR3) agonist lead series derived from (4‐phenyl‐1H‐imidazol‐2‐yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC50 = 5.2 nM, MW = 359). The results from molecular overlays of 5c onto the L‐129 crystal structure indicate good alignment, and two main differences of the proposed overlays of the antagonist MK‐4256 onto the conformation of 5c lead to inversion of antagonism to agonism. Keywords: Somatostatin Receptor 3; SSTR3; agonist; (4‐phenyl‐1H‐imidazol‐2‐yl)methanamine; structural overlay 1
Corresponding author: Tel: +1‐908‐740‐5258; e‐mail: [email protected] 104 Poster #58 Design and SAR of Next Generation of Potent, Selective, and Non‐covalent BTK Inhibitors Wendy Lee*, James J. Crawford, Kelly De La Torre, Hans Purkey, Charles Eigenbrot, Adam R. Johnson, Arna Katewa, Lichuan Liu, Harvey Wong, Christine Yu, Wendy B. Young Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 [email protected] Bruton’s tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases that functions downstream of multiple receptors in various hematopoietic cells. BTK plays a critical role in B‐cell maturation and survival in addition to regulating myeloid cell inflammatory cytokine production, making it an attractive target for the treatment of immunological disorders such as rheumatoid arthritis (RA) and lupus, as well as B‐cell malignancies. We have previously disclosed highly potent, selective, non‐covalent BTK inhibitors that have proven to be efficacious in rodent models of RA and lupus. In this poster, we will show design of a new generation of potent and selective BTK inhibitors with the primary goal of improving solubility. Detailed structure‐activity relationship (SAR) and synthetic details will be discussed. 105 Poster #59 Identification of Novel Constrained Peptides Which Exhibit Glucagon‐Like Peptide‐1 Receptor (GLP‐1R) Agonism Chris Limberakis†,¥*, Gary E. Aspnes†,‡, David R. Derksen‖,¥, David J. Edmonds†,‡, Heather Eng‖,¥, David P. Fairlie§, Gilles H. Goetz†,¥, Ariamala Gopalsamy†,‡, David A. Griffith†,‡, Timothy A. Hill§, Huy N. Hoang§, Amit S. Kalgutkar‖,‡, W. Mei Kok§, Spiros Liras†,‡, Alan M. Mathiowetz†,‡, Justin M. Mitchell§, Vincent Mascitti†,¥, David W. Piotrowski†,¥, David A. Price†,‡, Charles J. Rotter‖,¥, Roger B. Ruggeri†,‡, Kun Song†,‡, Robert V. Stanton†,‡, Jacky Y. Suen§, and Jane M. Withka‖¥ †Pfizer Worldwide Research and Development: Worldwide Medicinal Chemistry and ‖
Pfizer Worldwide Research and Development: Pharmacokinetics, Dynamics, and Metabolism, ‡Cambridge, MA, 02139 and ¥Groton CT 06340, United States. §Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane Qld 4072, Australia. [email protected] It is estimated that 415 million people are inflicted with type 2 diabetes (T2D) worldwide with numbers rising to 642 million by 2040. Because of this epidemic, significant efforts have been mobilized to battle this metabolic disease. One approach involves the development of glucagon‐like peptide‐1 (GLP‐1) receptor agonists. GLP‐1 is a naturally occurring hormone which potentiates glucose dependent insulin secretion and inhibits pancreatic ‐cell apoptosis. In addition, this hormone decreases food intake and gastric emptying which can lead to body weight reduction. As part of our GLP‐1 receptor agonist program, we pursued orally available agonists starting from the known 11‐mer peptide agonist 1. We designed and synthesized novel 11‐mer analogs with a focus on constrained peptides, because they can exhibit improved pharmacological and pharmacokinetic properties over their acyclic counterparts. One of the compounds synthesized was lactam 2 which retained significant agonist potency. 106 Poster #60 Synthesis, Identification and Biological Evaluation of 20S,23S‐Dihydroxyvitamin D3 as a Natural Vitamin D3 Metabolite of CYP11A1 Zongtao Lin†, Srinivasa R. Marepally†, Dejian Ma†, Tae‐Kang Kim‡, Allen SW. Oak‡, Linda K. Myers¶, Robert C. Tuckey§, Andrzej T. Slominski‡,∥, Duane D. Miller†, Wei Li†,* †Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States; ‡Department of Dermatology, University of Alabama at Birmingham, VA Medical Center, AL 35294, United States; ¶Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States; §School of Chemistry and Biochemistry, University of Western Australia, Crawley, WA 6009, Australia; ∥VA Medical Center at Birmingham, Birmingham, AL 35294, United States First author: [email protected]; *Corresponding author: [email protected] The vitamin D3 metabolite, 20S,23S‐dihydroxyvitamin D3, was chemically synthesized for the first time, and identified to be the same as the enzymatically produced metabolite by MS spectra, HPLC chromatograms and NMR spectra. The synthesis was carried out by a 13‐step route with an overall yield of 1.5%. The C23 absolute configurations of both 20S,23S/R‐
dihydroxyvitamin D3 epimers were unambiguously assigned by comparison of NMR spectra and Mosher ester analysis of intermediates. Their metabolism kinetics of CYP27B1 metabolism were investigated during the production of their 1α‐hydroxylated derivatives. Bioactivities of these metabolites together with their 1α‐OH derivatives were evaluated and compared in terms of vitamin D receptor activation, anti‐inflammatory and anti‐proliferative activities. The results showed that 1α‐OH can significantly potentiate the activities of the parent compounds, in addition, all compounds showed promising anti‐inflammatory activities. 107 Poster #61 Discovery of Orally Bioavailable and Liver Targeted Hypoxia‐Inducible Factor Prolyl Hydroxylase (HIF‐PHD) Inhibitors for Anemia Ping Liu,*1 Liping Wang,1 Byron G. DuBois,1 John Tan,1 Yili Chen,1 Ming Wang,1 Zack Guo,1 Vincent J. Colandrea,1 Rongqiang Liu,1 Jiaqiang Cai,9 Xiaoxing Du,9 Weiguo Quan,9 William Morris,2 Jianwu Bai,5 Bimjhana Bishwokarma,5 Mangeng Cheng,6 Jennifer Piesvaux,6 Kallol Ray,6 Chi‐Sung Chiu,7 Mark Zielstorff,7 Joseph M. Metzger,7 Liming Yang,7 Stella H. Vincent,8 Vincenzo Pucci,8 Xiaofang Li,8 Dennis Leung,3 Candice Alleyne,3 Alejandro Crespo,4 Domi Stickens,5 Jeffrey J. Hale,1 Feroze Ujjainwalla,1 and Christopher J. Sinz1 Department of 1Medicinal Chemistry, 2Discovery Process Chemistry, 3Basic Pharmaceutical Sciences, 4CM & I, Merck Research Laboratories, Rahway, NJ 07065; 5
Immunology, 6In Vitro Pharmacology, 7In Vivo Pharmacology, 8Drug Metabolism, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA ; 9WuXi PharmaTech, No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China Hypoxia‐Inducible Factor Prolyl Hydroxylase (HIF‐PHD) inhibitors act as hypoxia mimetics by stabilizing the transcription factor HIF, which modulates numerous genes leading to the transcription of proteins that stimulate erythropoiesis. Proof‐of‐concept for the treatment of anemia in patients with chronic kidney disease has been achieved for this mechanism with Fibrogen’s systemic small molecule HIF‐PHD inhibitors FG‐2216 and FG‐4592. HIF‐PHD inhibitors have pleiotropic effects and in order to mitigate the potential risk for undesired systemic effects, we pursued liver‐targeted HIF‐PHD inhibitors. This presentation will describe our medicinal chemistry efforts that led to the discovery of a novel series of hydroxy pyridone HIF‐PHD inhibitors with excellent potency and liver selectivity. We have demonstrated that liver‐specific inhibition of HIF‐PHD drives useful increases in red blood cell mass (hematocrit) separate from broad systemic effects. 108 Poster #62 Development of a selective inhibitor targeting the BRG1/BRM bromodomain a
b,d
Yangbing Li, Liu Liu, Chao‐Yie Yang, b,d and Shaomeng Wanga,b,c,d a Departments of Medicinal Chemistry, b Department of Internal Medicine, c Department of Pharmacology, and d Comprehensive Cancer Center University of Michigan, Ann Arbor, Michigan 48109, United States [email protected] The bromodomain–containing proteins BRG1 and BRM are the catalytic subunit of the mammalian SWI/SNF chromatin‐remodeling complex. SWI/SNF complex performs important roles in gene regulation, cell lineage specification and organismal development1. Recent study has shown a crucial role of the BRG1/BRM bromodomain during the differentiation of stem cells, suggesting that an inhibitor targeting the bromodomain of BRG1/BRM may affect cancer stem cell maintenance and differentiation2. In this study, a small molecule with weak binding affinity (Kd=100 M) to BRG1/BRM bromodomain was identified based on the core structure of PFI‐33. The co‐crystal structure of the inhibitors with BRM bromodomain indicated that the small molecule inhibitors could deeply bound into the acetyl lysine binding pocket. And an inhibitor with sub‐micromolar binding affinity to BRG1/BRM bromodomain was developed by further chemical modifications and SAR study. 1. Hohmann, A. F.; Vakoc, C. R. Trends Genet., 2014, 30, 356; 2. Fedorov, O.; Castex, J.; Tallant, C.; Owen, D. R.; Martin, S.; Aldeghi, M.; Monteiro, O,; Filippakopoulos, P.; Picaud, S.; Trzupek, J. D.; Gerstenberger, B. S.; Bountra, C.; Willmann, D.; Wells, C.; Philpott, M.; Rogers, C.; Biggin, P. C.; Brennan, P. E.; Bunnage, M. E.; Schüle, R.; Günther, T.; Knapp, S.; Müller, S. Sci. Adv. 2015, 1, e1500723; 3. http://www.thesgc.org/chemical‐probes/PFI‐3 109 Poster #63 Discovery of Dual‐Action Inhibitors Targeting Histone Deacetylases and Cyclin D Kinase 4/6 against Malignant Diseases Yongtao Li, Qingxiang Guo, Zhi Huang, Chao Zhang, Tianqi Wang, Shengyong Yang, Yan Fan* and Rong Xiang* School of Medicine, Nankai University, Tianjin 300071, PR China * Corresponding authors: [email protected], [email protected] Histone deacetylases (HDACs) catalyze the deacetylation from lysine residues in the N‐terminal ends of nucleosomal histones, leading to chromatin condensation, thus controlling the transcriptional activity of numerous genes often associated with the onset of cancer. Cyclin‐
dependent kinases 4 and 6 (Cdk4/6) are important components of cell cycle activation and control in early G1 phase. In our study, a series of novel dual‐action compounds were designed and synthesized to target HDAC and CDK4/6. In vitro kinase profiling revealed that the most active compound Roxyl‐LC5 was a multikinase inhibitor with excellent inhibitory activity of CDK4 (IC50 =8.8nM) and inhibitory activity of HDAC1 (IC50 = 2.2nM). The lead compound can induce apoptotic death of a wide variety of human tumor cell lines at nanomolar concentrations and show a significant increase in the percentage of cells in G1 as little as nanomolar. Our work represented a novel approach in the development of new chemotherapy for the treatment of malignant diseases. 110 Poster #64 Identification of Selective Ligands targeting Breast Cancer Stem Cells by Using Combinatorial Chemical Library Chao Long, Luxi Chen, Jiyong Lee University of Texas at Dallas Although breast cancer can be treated with advanced therapies, it is capable of reoccurring. Studies have shown that a subpopulation of tumor cells, termed cancer stem cells (CSCs), leads to recurrence or metastasis. CSCs possess tumorigenicity, drug resistance, and ability to self‐
renew and differentiate. By different cell surface markers, CSCs have been detected and isolated from various cancers including breast cancer. In breast cancer, cells with a CD44+/CD24‐
/low
phenotype are regarded as breast CSCs. EpCAM and aldehyde dehydrogenase (ALDH) are also used for the identification of Breast CSCs. To discover a new method to minimize breast cancer relapse, we aim to identify ligands that specifically target BCSCs and discover the ligands’ biological activities. Here, we present the isolation of novel ligands that specifically bind to breast cancer cells with a CD44+/CD24‐/EpCAM+ phenotype. Various in vitro and in vivo assays were used to test their activity in regulating CSC function. 111 Poster #65 Preparation and Biological Evaluation of BACE1 Inhibitors with trans‐Cyclopropylamide Linker Jose E. Lopez, James E. Audia, Leonard N. Boggs, Anthony R. Borders, Robert D. Boyer, Richard A. Brier, Pablo Garcia Losada , Stephen J. Green, Patrick C. May, Brian M Mathes, Dustin J. Mergott, Scott A. Monk, Stephanie L. Stout, David E. Timm, Brian M. Watson, Leonard L. Winneroski Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285 [email protected] We previously reported on the fragment‐based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF A in a Phase I clinical trials. We also reported on the discovery of LY2886721, a potent BACE1 Inhibitor that reached phase 2 clinical trials. In this presentation, a series of constrained BACE1 inhibitors containing a trans‐
cyclopropylamide linker will be disclosed. The trans‐cyclopropane core was assembled via an organocatalytic ammonium ylide induced cyclopropanation. Titanium (IV) ethoxide catalyzed [3 +2] cyclization of the trans‐cyclopropane intermediate with N‐(4‐methoxybenzyl)hydroxylamine afforded a cis‐fused tetrahydro‐furo[3,4‐c]isoxazole system with four contiguous chiral centers as a 2:1 diastereomeric mixture. This cis‐fused intermediate was converted into a bicyclic aminothiazine in three steps and the trans‐cyclopropylamide final products were prepared via amide coupling. The design, preparation, and biological activity of these BACE1 inhibitors will be presented. 112 Poster #66 Design, Synthesis, Protein Crystallography, and Biological Evaluation of BACE1 Inhibitors Using Multiple Types of Conformational Restriction to AchieveEnzyme and Cellular Potency Warren J. Porter, James P. Beck, Leonard N. Boggs, Anthony R. Borders, Robert D. Boyer, Richard A. Brier, Erik J. Hembre, Jon A. Erickson, Christopher S. Galka, Pablo Garcia‐
Losada, Steven J. Green, Jose E. Lopez, Brian M. Mathes, Patrick C. May, Dustin J. Mergott, Scott A. Monk, Zoran Rankovic, Yuan Shi, Stephanie L. Stout, David E. Timm, Brian M. Watson, and Leonard L. Winneroski Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285 [email protected] We previously reported on the fragment‐based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF A in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 Inhibitor that reached phase 2 clinical trials. Herein we describe a series of conformationally restricted BACE1 inhibitors containing a cis‐fused [4,5]‐pyrrolidine‐aminothiazine and trans‐cyclopropyl moieties used to achieve enzyme and cellular potency. An organocatalytic ammonium ylide induced cyclization afforded the desired trans‐cyclopropyl group. Titanium (IV) ethoxide catalyzed [3+2] cyclization of the trans‐cyclopropane intermediate with N‐(4‐methoxybenzyl)hydroxylamine afforded a cis‐
fused pyrrolo[3,4‐c]isoxazole system with four contiguous chiral centers as an ~2:1 diastereomeric mixture. The isoxazole intermediate was processed in three steps into a versatile tri‐protected cis‐fused [4,5]‐pyrrolidine‐aminothiazine containing a trans‐cyclopropyl ester. Details of the stereochemically complex organic synthesis as well as in vitro and in vivo biological evaluation will be presented. 113 Poster #67 Synthesis, molecular docking study and in vitro anticancer activity of tetrazole linked benzochromene derivatives Suresh Maddila1*, Sridevi Gorle2, Moganavelli Singh2, Parvesh Singh1, Sreekantha B Jonnalagadda2 1
School of Chemistry & Physics, University of KwaZulu‐Natal, Westville Campus, Private Bag X 54001, Durban‐4000, South Africa; 2Non‐viral gene delivery laboratory, Discipline of Biochemistry, University of KwaZulu‐Natal, Chiltern Hills, Durban‐ 4000, South Africa [email protected] A novel series of tetrazole linked benzochromene derivatives (3a–k) are synthesized in this work. This new class of compounds (11) gave good yields and were identified with 1H NMR, 15N NMR, 13C NMR, FT‐IR and HR‐MS spectrum. These protocols were subjected to possible potential antitumour activity in vitro in four human cancer cell‐lines (MCF‐7, Caco‐2, HeLa and SKBR‐3), and one human non‐cancer cell‐line (HEK293), using the MTT cell viability assay. Three compounds possessing the greatest cytotoxicity activity with IC50 values relative to that of 5‐
Fluorouracil, indicating the potential to be antitumor agents. Five compounds showed moderate activity. Additionally, a molecular docking analysis was conducted to predict the multi‐drug resistance (MDR) modulator behavior of synthesized compounds in the ATP binding site of P‐glycoprotein (P‐gp). The results obtained suggested good binding affinity of the compounds for the P‐gp based on the computed binding energies. Predominantly, electrostatic and hydrophobic interactions played significant role in their host‐guest relationship. 114 Poster #68 Novel Mcl‐1 selective small‐molecule inhibitors as a promising targeted therapy for multiple myeloma Ahmed Mady1,2, Lei Miao1,2, Karson Kump1, Katherine Lev1, Zaneta Nikolovska‐Coleska1,2 1
2
Departments of Pathology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI [email protected] Mcl‐1 is highly up regulated in multiple myeloma (MM) samples of patients, it contributes to MM pathogenesis and correlates with resistance to chemotherapy and shorter survival. The role of Mcl‐1 in regulating the apoptotic pathway was investigated in a panel of MM cell lines by using a new class of Mcl‐1 inhibitors. Applying de‐novo structure‐based drug‐design we have optimized and developed potent and selective inhibitors (Ki = 7 nM). Mechanistic studies demonstrated that these compounds selectively antagonize Mcl‐1 function, have on‐target activity and induce Bax/Bak dependent apoptosis. One of the most sensitive cell lines, H929, was determined that its survival depends on Mcl‐1 using BH3 profiling. These results demonstrate the therapeutic potential of Mcl‐1 inhibitors against multiple myeloma and lay a foundation for future preclinical studies. 115 Poster #69 Avoiding Missed Opportunities by Analysing the Sensitivity of our Decisions Tamsin E. Mansley, Iskander Yusof, Edmund J. Champness and Matthew D. Segall Optibrium Ltd., 7221 Cambridge Research Park, Beach Drive, Cambridge, CB25 9TL, UK [email protected] Drug discovery is a multi‐parameter optimisation process, in which the goal of a project is to identify compounds that meet multiple property criteria required to achieve a therapeutic objective. However, having chosen a profile of property criteria, their impact on the decisions made regarding progression of compounds or chemical series should be carefully considered. In some cases, the decision will be very sensitive to a specific property criterion and such a criterion may be artificially distorting the direction of the project; any uncertainty in the ‘correct’ value or the importance of this criterion may lead to valuable opportunities being missed. In this paper, we will describe a method for analysing the sensitivity of the prioritisation of compounds to a multi‐parameter profile of property criteria. We show how the results can be easily interpreted and illustrate how this analysis can highlight new avenues for exploration. 116 Poster #70 Development of Selective Inhibitors of Aggrecanase 1 and 2 for the Treatment of Osteoarthritis: Exploitation of Structural Features in the S1’ Site to Achieve Selectivity. Timothy B. Durham; Jothiraja Marimuthu; James L. Toth; Chin Liu; Lisa Adams; Craig Swearingen; Chaohua Lin; Mark G. Chambers; Kannan Thirunavukkarasu; and Michael R. Wiley Eli Lilly and Company. Lilly Corporate Center, Indianapolis, IN, 46285 [email protected] Aggrecanase 1 and 2 (ADAMTS‐4 and ADAMTS‐5) are zinc metalloproteases involved in the degradation of aggrecan, the compressible element of cartilage. Inhibitors of the aggrecanase enzymes could potentially provide a means of altering the progression of osteoarthritis. Here we report that selective hydantoin inhibitors of the aggrecanases can be designed by exploiting subtle residue differences in the S1’ binding site relative to several matrix metalloproteases. Inhibitors with selectivities of up to 50,000 fold against related matrix metalloproteases were achieved using this design approach. These compounds had good oral pharmacokinetics in rats and were shown to be efficacious in a rat chemical model of OA. 117 Poster #71 Unsymmetrical Nutlin‐3a analogs for treatment of retinoblastoma Anand Mayasundari,‡ Eleanor Pritchard,‡ Jaeki Min,‡ Brandon A. Vara,† Kristin Finch,‡ Christy R. Grace,‡ David Ban,‡ Nagakumar Bharatham,‡ Gloria Holbrook,‡ Fangyi Zhu,‡ Jeffrey N. Johnston,† Donald Bashford,‡ Richard W. Kriwacki,‡ Michael A. Dyer,‡ and R. Kiplin Guy ‡ ‡Department of Chemical Biology and Therapeu cs, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, United States; †Department of Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, 7330 Stevenson Center, Nashville, Tennessee 37235, United States [email protected] The p53 pathway is disrupted in virtually every human cancer, including retinoblastoma, the most common malignant cancer of the eye in children. The interaction of p53 with its negative regulators MDM2 and MDMX plays a critical role in regulating the cell cycle. MDM2 and MDMX function by binding the p53 protein and negatively regulating its transcriptional activity and stability. Inhibition of the MDM2/X‐p53 interaction results in the stabilization of p53, cell cycle arrest and apoptosis. Applying a catalytic, enantioselective route we synthesized unsymmetrical Nutlin‐3a analogs as novel MDM2/X inhibitors for the treatment of retinoblastoma. This is the first application of this strategy to synthesize unsymmetric cis‐imidazolines to obtain not only structural novelty, but also potency and is based on a key aza‐Henry reaction and a highly selective bifunctional organocatalyst. Highly promising preclinical pharmacokinetics data has helped us identify novel Nutlin‐3a analogs that show promise as therapeutic candidates for retinoblastoma. 118 Poster #72 Design, synthesis and application of novel building blocks to “Escape the Flatland” in medicinal chemistry Bandak, D.; Dmytriv Y.; Komarov, I.; Kokhan, S.; Korolyov, O.; Mitiuk, A.; Mykhailiuk, P.; Pavlenko, S.; Tolmachev, A.; Tymtsunik, A. Enamine Ltd, 78 Chervonotkatska Street, 02094 Kyiv, Ukraine Given the modern trend in medicinal chemistry – “Escape the Flatland”1 – saturated 3D‐shaped building blocks do play an important role.2 Compared to their aromatic 2D‐shaped counterparts, the saturated analogues usually possess higher water solubility, higher activity and lower toxicity. O
Br
CO2H
CO2H
CF3
CO2H
AcO
CO2H
NH2
CF3
NH2
F3C
Br
OTos
H2N
HO2C
MeO2C
O
CO2H
CO2H
Escape
the Flatland
CF3
NH2
CO2H
2D-shaped
aromatic
CO2H
CO2H
3D-shaped
saturated
F
NH2
O
CO2H
HO2C
CO2H
MeO2C
CO2H
CF3
NH2
NH2
CO2H
OH
In this work, therefore, we have rationally designed and synthesized a library of novel saturated bioisosters of benzene. Details of the synthesis and application of the obtained compounds will be discussed.3‐5 1
F. Lovering et al. J. Med. Chem.2009, 6752. A. F. Stepan et al. J. Med. Chem.2012, 3414. 3 D. Bandak et al. Org. Lett. 2015, 226. 4 P. Mykhailiuk et al. J. Fluorine Chem. 2010, 217. 5 P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2006, 5659. 2 119 Poster #73 Synthesis and application of unnatural Proline analogues: advanced building blocks for medicinal chemistry Bilenko, V.; Dolovanyuk, V.; Grygorenko, O.; Ivon, Y.; Komarov, I.; Kondratov, I.; Kubyshkin, V.; Leychenko, E.; Michurin, O.; Mykhailiuk, P.; Savchuk, T.; Tereshenko, S.; Tolmachev, A.; Trofymchuk, S.; Tymtsunik, A.; Vilchinskiy, V. Enamine Ltd, 78 Chervonotkatska Street, 02094 Kyiv, Ukraine L‐Proline is a natural amino acid playing an important role in drug discovery as a cheap chiral bifunctional building block. In this context, over the past decade unnatural analogues of Proline also became extremely popular. For example, in 2010 Gilead launched Ledipasvir – a drug bearing the residues of two unnatural analogues of L‐Proline. F
F
N
N
CO2H
N
H
N
H
O
N
NH
MeO2C
L-Proline
N
H
O
Ledipasvir
Gilead
anti-hepatitis drug
N
H
CO2H
N
H
F
F
CO2H
CO2H
N
H
N
H
CO2H
MeO
CO2H
N
Boc
N
H
HN
CO2Me
CO2H
F
CF3
CF3
CO2H
N
Boc
CO2H
N
H
N
H
CO2H
CF3
N
H
CO2H
N
N
H
F
CO2H
O
N
H
CO2H
CO2H
N
H
H
N
H
CO2H
H
N
H
CO2H
N
H
CO2H
N
H
CO2H
N
H
H
CO2H
N
H
CO2H
N
H H
CO2H
In this work, we have rationally designed, synthesized and applied a library of novel/previously scarcely available analogues of Proline in medicinal chemistry. Details of the synthesis and application of the obtained compounds will be discussed.1‐9 1 V. Kubyshkin et al. Org.Biomol.Chem. 2015, 13, 3171; 2 A. Tymtsunik et al. Tetrahedron Lett. 2014, 53, 3847; 3 V. Kubyshkin et al. Org. Lett. 2012, 14, 5254; 4 I. Kondratov et al. Org.Biomol.Chem. 2012, 10, 8778; 5 P. Mykhailiuk et al. Tetrahedron 2011, 67, 3091; 6 V. Kubyshkin et al. Synthesis 2009, 3327; 7 P. Mykhailiuk et al. Angew.Chem.Int.Ed. 2008, 47, 5765; 8 V. Kubyshkin et al. Tetrahedron Lett. 2007, 48, 4061; 9 O. Grygorenko et al. Tetraheron: Asymm. 2006, 17, 252. 120 Poster #74 Discovery of MK‐8831, A Novel Spiro‐proline Macrocycle as a Pan‐Genotypic HCV‐NS3/4a Protease Inhibitor Santhosh F. Neelamkavil,* Sathesh Bhat, Dipshikha Biswas, Linda Brockunier, Samuel Chackalamannil, Mariappan Chelliah, Austin Chen, Ian W. Davies, Zhuyan Guo, Yongxin Han, Shouwu Miao, Andrew Nolting, Rebecca T. Ruck, Unmesh Shah, Francisco Velazquez and Srikanth Venkatraman Merck Research Laboratories, Kenilworth, New Jersey 07033, United States Approximately 170‐200 million people worldwide are chronically infected with hepatitis C virus (HCV) with majority infected by genotype 1 (~70% of all cases of HCV in United States), 2 and 3. For several years the standard of care was pegylated interferon plus rivabarin with poor cure rates, long treatment periods and difficult side effects. Multiple oral drugs with shorter treatment regimen have recently been approved for the treatment of HCV patients including Zepatier™ from Merck which has shown impressive cure rates in the clinic with excellent safety profile. Zepatier™ is a combination of NS3/4a protease inhibitor (MK‐5172) and a NS5A inhibitor (MK‐8742) and we have been working on a back‐up to MK‐5172 with the goal of improving on the pan‐genotypic activity. This presentation will highlight the structure based design and SAR on a novel spiro‐proline macrocycle leading to the discovery of a potent pan‐
genotypic NS3/4a protease inhibitor MK‐8831. 121 Poster #75 Synthesis and Behavioral Studies of Chiral Cyclopropanes as Selective α4β2‐Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile a,e
Oluseye K. Onajole, Gian Paolo Vallerini,a J. Brek Eaton,b Ronald J. Lukas,b Dani Brunner,c Barbara J. Caldarone,d and Alan P. Kozikowskia a
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; bDivision of Neurobiology, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ 85013, United States; cPsychoGenics, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591, USA; dHarvard NeuroDiscovery Center and Department of Neurology, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; eDepartment of Biological, Chemical and Physical Sciences, Roosevelt University, 425 S. Wabash Avenue, Chicago, IL 60605, USA Herein, we report the synthesis and biological characterization of novel derivatives of 3‐[(1‐
methyl‐2(S)‐pyrrolidinyl)methoxy]‐5‐cyclopropylpyridine (4a‐f and 5) as potent and highly selective α4β2‐nicotinic acetylcholine receptor (nAChR) full or partial agonists. A systematic structure‐activity study was carried out on the previously described compound 3b, particularly concerning its (2‐methoxyethyl)cyclopropyl side‐chain, in an effort to improve its metabolic stability while maintaining receptor selectivity. Compound 4d exhibited very similar subnanomolar binding affinity for α4β2‐ and α4β2*‐nAChRs compared to 3b, and it showed excellent potency in activating high‐sensitivity (HS) α42‐nAChRs with an EC50 value of 8.2 nM. Testing of 4d in the SmartCube® assay revealed that the compound has a combined antidepressant plus antipsychotic signature. In the forced swim test at a dose of 30 mg/kg given intraperitoneally, 4d was found to be as efficacious as sertraline, thus providing evidence of the potential use of the compound as an antidepressant. 122 Poster #76 Developing Small Molecule Activators for Ring‐Between‐Ring E3 Ubiquitin Ligase PARKIN a,b
b
Sungjin Park , Peter. K. Foote , David T. Kristb, Alexander V. Statsyukb and Sarah E. Ricea a
Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, United States; b Chemistry of Life Processes Institute, Department of Chemistry, Northwestern University, Silverman Hall, 2145 Sheridan Road, Evanston, Illinois 60208, United States. The PARKIN E3 ligase is implicated in selective degradation of damaged mitochondria via autophagy (mitophagy). Failure of timely clearance of damaged mitochondria has been linked to the pathogenesis of Parkinson’s disease (PD). Therefore, activating PARKIN may be a viable therapeutic strategy for Parkinson’s disease. A major roadblock for developing PARKIN activators is the intrinsic complexity and limited readout of reconstituted native cascade ubiquitination reactions. Here we used a simple chemical probe, ubiquitin C‐terminal fluorescein thioester (UbFluor), to quantitatively assess PARKIN activity in real time using fluorescence polarization. We confirmed that UbFluor quantitatively detects naturally‐occurring activation of PARKIN caused by Ser65‐phosphorylation and binding to phosphorylated ubiquitin. Using UbFluor‐based high‐throughput screening assay with ChemBridge/ChemDiv libraries, we identified both activators and inhibitors for PARKIN. Those hit molecules are currently under secondary validation process. 123 Poster #77 Molecular design and synthesis of chromenopyridines as anti‐fibrotic agents Renukadevi Patil1, Anandita Ghosh2, Phoebus Sun Cao3, Kyle Grice3, Gulam Waris2, Shivaputra Patil1 Pharmaceutical Sciences Department, College of Pharmacy, 2Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064; 3Department of Chemistry, College of Science and Health, DePaul University, 1110 W. Belden Ave, Chicago, IL 60614. 1
Hepatocellular carcinoma (HCC) is a worldwide health problem, ranking as the fifth most common cancer. HCC accounts for approximately 600,000 deaths annually worldwide and 10,000 deaths in the United States. Chronic infection with the hepatitis C virus (HCV) is the second most important risk factor for HCC. HCV infection causes chronic hepatitis, liver fibrosis, cirrhosis and HCC. Liver fibrosis is a reversible wound healing response to chronic liver injury which if persistent can lead to cirrhosis and liver cancer. Development of new therapies for liver cancer and chronic liver diseases associated with viral Hepatitis C remains a critical challenge. Identification of novel anti‐fibrotic compounds will provide opportunities for novel therapeutic intervention of HCV‐mediated liver cancer. We designed and synthesized novel chromenopyridines and screened them for their anti‐fibrotic activity using human hepatic stellate cells (HSCs). Interestingly, we identified a novel chromenopyridine analog as a potential hit. 124 Poster #78 Fingolimod Phosphoroamidate Prodrugs for potential treatment of Multiple Sclerosis Fabrizio Pertusati,1 Edward Langhorne,1 Katharina Saueberli,2 Yves Barde2 and Christopher McGuigan1 1
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK; 2School of Biosciences, Cardiff University, The Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK Neurological conditions are on the increase, but drug approvals are few, with new promising leads urgently required. A recent breakthrough in Multiple Sclerosis (MS) treatment is Fingolimod, approved by the FDA as the first oral disease‐modifying agent for MS. In vivo, Fingolimod is phosphorylated to form Fingolimod‐phosphate (Fingolimod‐P), which exerts its therapeutic effects through modulation of sphingosine 1‐phosphate receptors. Very recently, researchers have reported that Fingolimod may also act in the brain by other mechanisms1. Remarkably, in every case the active form is Fingolimod monophosphate. Our ProTide approach has been very successful in the delivery of drugs monophosphate, several of which are now in clinical trials and in the market as anticancer and antiviral agents. In this poster, we report our preliminary finding in the synthesis of Fingolimod phosphoramidates. We will also show that in vitro activation of these prodrugs leads to the delivery of the Fingolimod monophosphate as evidenced by enzymatic experiments monitored by 31P NMR. 1. Nat. Neurosci. 2014, 17,971‐980; Learn Memory 2007, 14, 268‐276. 125 Poster #79 Copper‐catalysed diastereoselective synthesis of P‐chiral phosphoramidate prodrugs (ProTides) Elisa Pileggi, Fabrizio Pertusati, Andrea Brancale, Christopher McGuigan School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3AX, UK [email protected] Nowadays, drug chirality represents a major theme in the discovery and development of new drugs. Currently, FDA’s policy requires promoting chiral separation and assessment of each isomer activity in the body for the optimal treatment of the patient.1 Our phosphoroamidate prodrug approach (ProTide) has been very successful in delivery nucleoside monophosphates, with several drugs now in clinical trials and even in the market. So far, the large majority of ProTides have been progressed to the clinic as diastereoisomeric mixtures. The most significant exception is represented by Sofosbuvir, approved by FDA for HCV treatment and marketed as single diastereoisomer (Sp). Consequentely, our work aims to develop a general procedure for the diastereoselective synthesis of phosphoramidate prodrugs of nucleoside analogues. The highlighted synthetic approach is totally novel in the scenario of drug synthesis and will have the enormous potential to be applied to the wide areas of asymmetric phosphorus chemistry. 1. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122
883.htm 126 Poster #80 Tumor‐Targeting Alkyl Phospholipid‐Drug Conjugates Anatoly N. Pinchuk, Marc A. Longino, Kevin Kozak, Chorom Pak, Nathan W. Stehle, Kris Lange, Sandeep Nair, Jamey P. Weichert* Cellectar Biosciences, Madison, WI 53716 [email protected] An alkyl phosphocholine (APC) analog, CLR1401 (18‐p‐(iodophenyl)octadecyl phosphocholine, CLR1404), when radioiodinated with I‐124 or 131 for imaging and radiotherapy, undergoes selective uptake and prolonged retention in a variety of malignant tumors. The iodine can be replaced with fluorescent dyes for in vitro and in vivo imaging. To evaluate the potential of APC’s for targeted delivery of antitumor drugs, we synthesized several conjugates of various antitumor drugs with CLR1401. Preliminary results for three paclitaxel‐CLR1401 conjugates: CLR1601, CLR1602 and CLR1603, with ester, carbamate, and carbonate linkers, respectively, will be presented. A Cremophor EL®‐free excipient solution is used to formulate these agents. CLR1602 is the most stable in plasma and liver microsomes, while CLR1601 and CLR1603 are less stable. Accordingly, CLR1601 and CLR1603 portrayed efficacy in twelve cell lines, while CLR1602 did not. In vivo studies are ongoing to validate tumor targeting. O
O
O
O
O
O OH
O
NH O
O
O
OH
O
O
O
NH O
O
H
O
O
O
O
O
O OH
O
H
OHO O
O
O
O
CLR1601
CLR1603
O
O
HN
(CH2)18OPOCH2CH2NMe3
O
HN
O
H
N
O
O
O
O O
O
(CH2)18OPOCH2CH2NMe3
O
O
(CH2)18OPOCH2CH2NMe3
O
NH O
O
OH
OH
O
O
N
H
O
O
H
O
O
O
CLR1602
127 Poster #81 Development of oxidative stress inducing, GSTP1 inhibiting BBB penetrable small molecule and evaluation in glioblastoma models in vitro and in vivo Surendra R. Punganuru, Hanumantha Rao Madala and Kalkunte S. Srivenugopal Department of Biomedical Sciences and Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 S. Coulter Dr., Amarillo, TX 79106, USA [email protected] The incidence of primary brain tumors in adults and children has continued to increase in USA. However, these tumors remain highly intractable to therapy and prognosis remains dismal. There is an urgent and essential need to design new, more effective, tumor‐selective and BBB penetrating chemotherapy drugs that can advance the survival and quality of life for glioma patients. We approached this need by exploiting the elevated oxidative stress present in gliomas, and synthesized hydrophobic non‐diuretic analogs of ethacrynic acid, one of which (KSS‐72) is highly cytotoxic to GBM cells in culture and accumulates in the brain after intravenous or oral administrations. KSS‐72, whose major mechanism of action is to inhibit GSTP1 and trigger redox imbalance, was non‐toxic to normal cells. Further, KSS72 completely suppressed the growth of intracranial glioblastoma in nude mice with no discernible toxicity to the host tissues (supported by CPRIT grant RP130266). 128 Poster #82 Development of Novel Inhibitors of the Key Shigella flexneri Virulence Regulator Nicholas J. Ragazzone, Anthony A. Emanuele and George A. Garcia Department of Medicinal Chemistry, College of Pharmacy University of Michigan, Ann Arbor, MI 48109 [email protected] Shigella infections are the main cause of bacterial dysentery in humans. Infections lead to over one million deaths worldwide each year. VirF is a key transcriptional regulator that controls the expression of several virulence factors in Shigella. VirF is an attractive target for intervention because, while it is indispensable in the virulence pathway of Shigella, it is not required for bacterial viability, providing less pressure for the development of resistant strains. Our lab conducted a high‐throughput screen of ~140,000 small molecules to identify molecules that had potential to inhibit VirF. Five lead compounds were tested in tissue culture‐based invasion and plaque formation assays to determine their ability to prevent initial host cell infection and cell‐to‐cell spread. Of these hit compounds, one was determined to inhibit VirF by blocking the ability to bind DNA and two others shared a common core scaffold. An initial SAR was performed to determine preferred moieties. 129 Poster #83 Chemoproteomic Probes for the Keap1/Nrf2 Interactions Benjamin Richardson, Atul D. Jain, Terry W. Moore Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL, 60612 [email protected] Nrf2 is the chief transcription factor that regulates defenses against environmental stress. Under normal conditions, Nrf2 is sequestered in the cytosol by its negative regulator Keap1, which polyubiquitinates Nrf2, leading to proteosomal degradation. Nrf2 has become an important therapeutic target, as its misregulation is implicated in many disease states. To date, all clinical Nrf2 activators have been electrophilic compounds, directly modifying Keap1. While this mechanism of action produces the desired physiological effect, the electrophilic activators may be non‐selective. This trait produces difficulty in pinpointing if observed effects are solely due to Nrf2 activation or activation of multiple biological systems by reactive electrophiles. To contribute to the understanding of this issue, we have created non‐electrophilic photoprobes based on a reported naphthalene‐based activator that induces Nrf2’s transcriptional activity through direct inhibition of the Keap1/Nrf2 interaction. Through proteomics, we will ascertain the relative selectivity of non‐electrophilic Nrf2 activators. 130 Poster #84 Identification and Evaluation of Isothiazole‐Based Novel Nrf2 inducers Fumihiko Saitoh a, [email protected], Tomoyuki Kamino a, Motoi Nakahara a, Takashi Mizuno a Katsutoshi Takeuchi a, Yukari Arai a, Koji Chiyoda a, Masaki Kawamoto a, Yoshitaka Maeda a, Chika Higashi a, Makiko Hayashi b, Naoto Tsuda a, Atsuko Kawaji a, Takehiko Murai a, Kazuya Uchida a, Masatsugu Kamiya a, Hiroyasu Naba a, Kazunari Nakao a
, Shoji Furusako a, Akira Uruno b, Masayuki Yamamoto b a
Discovery Research, Mochida Pharmaceutical Co.,Ltd., 722 Jimba, Uenohara, Shizuoka, Japan; bDepartment of Medical Biochemistry, Tohoku University Graduate School of medicine, 2‐1 Seiryo‐machi, Aoba‐ku, Sendai, Japan Nrf2 (nuclear factor‐E2‐related factor‐2) is a redox‐sensitive transcription factor1 that plays important roles in anti‐oxidative pathways for tissue protection in chronic‐progressive multiple sclerosis.2 High throughput screening (HTS) campaign identified isothiazole‐containing hits as novel Nrf2 inducers. Hit‐to‐lead efforts were then ensured to identify a lead compound, TFM‐
735, with good properties for oral administration. Single administration of TFM‐735 to mice increased Nqo1 mRNA levels in spleen and brain. Multiple administration of TFM‐735 reduced the clinical scores compared to the vehicle in experimental autoimmune encephalomyelitis (EAE) in not only C57BL/6 mice but also hIL6‐BAC‐Luc transgenic ICR mice3 in which bioluminescence in the brain and spinal cord region was also reduced by treatment with TFM‐
735, suggesting that TFM‐735 is a promising agent for intervention of multiple sclerosis. In this presentation, assessment of TFM‐735 and the corresponding analogues as novel Nrf2 inducers will be described. X‐ray crystallographic structure of an analog with BTB‐IVR will be also disclosed. 1. Saito R.; Suzuki T.; Hiramoto K.; Asami S.; Naganuma E.; Suda H.; Iso T.; Yamamoto H.; Morita M.; Baird L.; Furusawa Y.; Negishi T.; Ichinose M.; Yamamoto M., Characterizations of three major cysteine sensors of Keap1 in stress response. Molecular and Cellular Biology 2016, 36: 271–284. 2. Arnold P.; Mojumder D.; Detoledo J.; Lucius R.;, Wilms H.; Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid‐2‐related factor 2 and emerging pathways. Clinical Pharmacology 2014, 6: 35–42. 3. Hayashi M.; Takai J.; Yu L.; Motohashi H.; Moriguchi T.; Yamamoto M., Whole‐body in vivo monitoring of inflammatory diseases exploiting human Interleukin 6‐luciferase transgenic mice. Molecular and Cellular Biology 2015, 35: 3590–3601. 131 Poster #85 Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase‐
Activating Compound 1 (PAC‐1) with Improved Pharmacokinetics Howard S. Roth1 and Paul J. Hergenrother2 1
Department of Chemistry, Yale University Department of Chemistry, University of Illinois at Urbana‐Champaign [email protected] Procaspase‐activating compound 1 (PAC‐1) is an ortho‐hydroxy‐N‐acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase‐3. PAC‐1 has been assessed in diverse cell culture experiments and in vivo tumor models, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half‐life of PAC‐1 could be limiting. Thus, with the goal of developing a compound with improved pharmacokinetics, a series of PAC‐1 analogues was designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head‐to‐head experiments with PAC‐1, pharmacokinetic evaluation in mice demonstrated extended elimination half‐lives and greater AUC values for each of the four compounds, suggesting them as promising candidates for further development. 2
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Adapted with permission from Roth, H.S., et al. Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase‐Activating Compound 1 (PAC‐1) with Improved Pharmacokinetics. J. Med. Chem. 2015, 58, 4046‐4065. Copyright © 2015 American Chemical Society. 132 Poster #86 New therapeutic agents for tuberculosis: Synthesis, SAR and pharmacological evaluation of pyrazolo[1,5‐a]pyrimidin‐7‐ols Shaik Azeeza, Andaleeb Sajid, Yoshitaka Tateishi, Danielle Weiner, Michael Goodwin, Helena I. Boshoff, Peter Ray, Via Laura, Clifton E. Barry III Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, United States In the development of new therapeutic agents for tuberculosis with novel mechanism of action to address the drug resistance crisis we synthesized a collection of new pyrazolo[1,5‐
a]pyrimidin‐7‐ols derivatives. These derivatives were evaluated against Mycobacterium tuberculosis grown in 7H9/glucose/glycerol/Tween/BSA and in GAST/Fe media to explore complete structure‐activity relationship studies. Amongst these four compounds (AS13‐3, AS13‐41, AS13‐50, and AS13‐55) have shown good in vitro activity (MIC ranging 0.3‐12.5 µM) and negligible toxicity in HepG2 cell lines with good kinetic solubility in PBS (pH 7.4) solution. To evaluate the in vivo activity of these compounds stability in mouse liver microsomes and pharmacokinetic properties have been studied in mice. The excellent PK parameters of these compounds have encouraged us to carry out in vivo studies at different doses and these are currently underway. In addition, preliminary investigations on the mechanism of action (and previous reports1) are suggesting that these compounds are inhibiting isoprenoid biosynthesis in M. tuberculosis which is a new and novel target. 1) Mao, J.; Eoh, H.; He, R.; Wang, Y.; Wan, B.; Franzblau, S. G.; Crick, D. C.; Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2008, 18, 5320. 133 Poster #87 A Novel Dendrimer‐Curcumin Formulation A. Sharma*, D. Swanson, K. Johnson, R. Uzarski Department of Chemistry & Biochemistry and Department of Biology Central Michigan University, Mt. Pleasant, MI 48859 [email protected] In spite of its medical importance, curcumin is extremely insoluble in water resulting in poor bioavailability. A popular solubilization strategy is the use of dendrimers. PAMAM dendrimers have excellent aqueous solubilites and can be tailor made in various sizes and surface chemistry to develop formulations with specific biological properties. In this report, we describe a novel way of encapsulating curcumin within the cavities of a G4 PAMAM dendrimer. In an attempt to maximize the amount of curcumin encapsulated in a single dendrimer, curcumin was first mixed with the ester G3.5 diaminobutane core in methanol. After allowing sufficient time for curcumin encapsulation, synthesis to its G4 was completed with ethanolamine to yield a formulation consisting of curcumin encapsulated within a generation 4 DAB core with biocompatible hydroxyl surface. The characterization, release kinetics and preliminary data on its effects on a pancreatic cancer cell line will be discussed. 134 Poster #88 LipE‐Guided Discovery and Development of Pantothenate Kinase Modulators Lalit Kumar Sharma1, 2, Chitra Subramanian1, Mi‐Kyung Yun3, Stephen White2, Suzanne Jackowski1, Charles O. Rock1, Richard E. Lee2 1
Department of Infectious Diseases, 2Department of Chemical Biology and Therapeutic, and 3
Department of Structural Biology, St. Jude Children’s Research Hospital [email protected] Pantothenate kinase (PanK) is a regulatory enzyme that controls coenzyme A (CoA) biosynthesis. The association of PanK with neurodegeneration and diabetes suggests that chemical modifiers of PanK activity may be useful therapeutics. Our high‐throughput screen and further medicinal chemistry efforts focused on optimizing lipophilic ligand efficiency (LipE) culminated in a novel class of orally bioavailable PanK inhibitors. Enzyme kinetics, biophysical studies, and X‐ray crystallography demonstrate that the inhibitor bind to the PanK‐ATP complex. These compounds either decrease or increase cellular CoA levels depending on the amount of pantothenate in the medium. We confirmed the activation/inhibition mode of these compounds in animal model. These nanomolar PanK modulators are being further developed as preclinical leads to validate PanK as a novel target to treat neurologic and metabolic disorders. 135 Poster #89 Evaluation of A Novel and Potent Uricosuric Agent Dongfang Shi*, Changjin Fu, Xi Cheng, Jianghu Zhu Jiangsu Atom Bioscience and Pharmaceutical Co. Ltd., Zhenjiang, China [email protected] Gout is caused by abnormally elevated levels of serum urate. It is linked to elevated hypertension and increased mortality in chronic kidney disease. There are approximately 8.3 million gout patients in the US, and 6.4 million in the EU. Only a small number of drugs are used for the medications of gout; some of those drugs such as benzbromarone, have severe side effects. We have designed and synthesized a new class of anti‐gout uricosuric compounds. Compound ABP‐606 has low MW and showed very low human liver cell toxicity in comparison with gout agents benzbromarone and lesinurad. ABP‐606 shows great inhibition of hURAT1, and its efficacy is equivalent to or better than benzbromarone in rat. ABP‐606 also demonstrates good profiles with plasma and microsomal stability, reasonable plasma protein binding, and good DMPK in rat. ABP‐606 could be a suitable preclinical candidate for the further development of a uricosuric agent. 136 Poster #90 Benzbromarone Analog As a Potent Uricosuric Agent for the Treatment of Gout 1*
1
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Dongfang Shi , Changjin Fu , Xi Cheng , Min Chang2, Jianghu Zhu1, Aihua Zhou2 1
Jiangsu Atom Bioscience and Pharmaceutical Co. Ltd., Zhenjiang, China; 2School of Pharmacy, Jiangsu University, Zhenjiang, China [email protected] Gout is a common cause of acute painful arthritis affecting an estimated 8.3 million people in the US. Benzbromarone or its combination with allopurinol significantly decrease serum urate levels in patients with gout. Benzbromarone is superior to allopurinol, probenecid and lesinurad; it suppresses the reabsorption of uric acid by kidney via inhibition of the main renal urate transporter 1(URAT‐1). However, benzbromarone has significant limitations due to the risk of severe hepatotoxicity, although it is still marketed in many countries. We have developed a new class of imidazo[1,2‐a]pyridin analogs of benzbromarone. Our approach towards the discovery of a preclinical candidate ABP‐601 may avoid the formation of major toxic metabolites quinones. The SAR of those compounds will be presented. Compound ABP‐
601 exhibits excellent in vitro and in vivo profiles with efficacy equivalent or better to benzbromarone with substantially less hepatotoxicity. ABP‐601 may be a suitable candidate for further clinical trials. 137 Poster #91 Design and Syntheses of Novel Fluorescent and Biotinylated Tocopherol Probes Zhen‐Dan Shi, Miao Xu, Biying Xu, Gary L. Griffiths, Wei Zheng, Rolf E. Swenson Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health [email protected] Niemann‐Pick type C (NPC) is a lysosomal storage disease caused by mutations of the NPC1 and NPC2 genes, which results in accumulation of unesterified cholesterol in lysosomes. Currently there are no FDA‐approved therapies for NPC. Recent studies showed that ‐tocopherol effectively decreased lysosomal cholesterol accumulation, reduced lysosomal volume and alleviated NPC pathological phenotype, while it also increased cholesterol efflux. In order to further investigate mechanisms of cell cholesterol trafficking, multiple new fluorescent tocopherol probes and biotinylated tocopherol probes were designed and synthesized. Some of the probes are cellular permeable and maintain pharmacological effects. The structural activity relationships we observed, on method and location of dye attachment, could lead to more specific compounds for the treatment of NPC, without some of the other side effects of ‐
tocopherol. Herein we present the detailed design, syntheses and biological testing results of the tocopherol probes. 138 Poster #92 Discovery of Purine‐based Inhibitors of Dual Leucine Zipper Kinase (DLK) for Neurodegenerative Indications Daniel G. M. Shore,* Snahel Patel, Anthony Estrada, Seth Harris, Paul Gibbons, Malcolm Huestis, Terry Kellar II, Joseph Lyssikatos, Jonathan Cheong, Brian Dean, Gauri Deshmukh, Amy Gustafson, Zhiyu Jiang, Yichin Liu, Xingrong Liu, Emile Plise, Amy Sambrone, Kimberly Scearce‐Levie, Young Shin, Hilda Solanoy, Kathy Wang, Peter Yin, Joseph Lewcock, Michael Siu Departments of Discovery Chemistry, Neuroscience, Drug Metabolism and Pharmacokinetics, and Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States [email protected] The discovery of disease‐modifying therapeutics for the treatment of neurodegenerative diseases continues to present a challenge for modern medicine. Dual Leucine Zipper Kinase (DLK) is an upstream regulator for the c‐Jun N‐terminal kinase (JNK) signaling pathway which is proposed to be implicated in neurodegeneration. Therefore, disruption of JNK pathway signaling through inhibition of DLK has the potential for neuroprotective effects. Herein we describe the discovery of brain‐penetrant, selective, purine‐based inhibitors of DLK that demonstrate robust in vivo pharmacodynamic effect in a rodent nerve injury model. 139 Poster #93 Synthesis, Docking and Antidiabetic Activity of Some Newer Benzamide Glucokinase Activators Ajmer Singh1, Rajeev Kharb2, Viney Lather1 1
Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa ‐ 125055, India; 2
CT Institute of Pharmaceutical Sciences, Jalandhar‐144020, Punjab, India Glucokinase (GK) is an enzyme that catalyzes conversion of glucose to glucose‐6‐phosphate. Due to its key role in glucose homeostasis, GK is a potential target for the treatment of type 2 diabetes. GK activators are the new class of drugs which act on GK enzyme and show their anti‐
diabetic activity. The present work involved the design and synthesis of newer benzamide derivatives and their evaluation by computational studies i.e. docking to determine the interactions of best fit conformations in the binding site of GK enzyme. Amongst the synthesized molecules, compounds 14 and 20 with phenyl‐substituted thiazole moiety on amide nitrogen, exhibited high activity. The experimental results were found to be in concordance with that of the docking studies. The molecular properties of these derivatives followed the Lipinski’s rule of five. Thus, these molecules can act as the starting hits for the design of new, safe, effective and orally bioavailable GK activatorss for the treatment of type 2 diabetes. Corresponding author: Ajmer Singh Jan Nayak Ch. Devi Lal Memorial College of Pharmacy, Sirsa ‐ 125055, India E‐mail: [email protected] 140 Poster #94 Inhibitors of HIV‐1 Maturation: Exploration of structure‐activity relationship (SAR) of C‐28 amines, based on C‐3 benzoic acid‐modified triterpenoids Sing‐Yuen Sit,* Yan Chen, Jie Chen, Jacob J. Swidorski, Zheng Liu, Ny Sin, Brian L. Venables, Dawn D. Parker, Beata Nowicka‐Sans†, Brian J. Terry, Tricia Protack, Sandhya Rahematpura, Umesh Hanumegowda, Susan Jenkins, Mark Krystal, Ira B. Dicker, Nicholas A. Meanwell, Alicia Regueiro‐Ren Pharmaceutical Research Institute, Bristol‐Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492‐7660, USA [email protected] As a part of our ongoing effort in the exploration of the SAR surrounding the C28 position of the C3 benzoic acid modified triterpenoids as HIV‐1 maturation inhibitors (MI). We have demonstrated that replacing the dimethyl succinate ester sidechain in Bevirimat (BVM) with a 4‐benzoic acid retained most of the key virological characteristics with the first generation compound. In this poster we will disclose our efforts in addressing other critical issues such as polymorphic coverage and serum binding effects with this design. 141 Poster #95 Branching Out: γ‐Methylated Hydrocarbon Stapled Peptides for the Estrogen Receptor/Coactivator Interaction Thomas E. Speltz,a Sean W. Fanning,b Christopher G. Mayne,c Colin Fowler,b Emad Tajkhorshid,c Geoffrey L. Greene,b Terry W. Moore a a
T. E., Speltz, Prof. T.W. Moore, Department of Medicinal Chemistry and Pharmacognosy and UI Cancer Center, University of Illinois at Chicago, 833 S. Wood St. Chicago, IL 60612 USA; bDr. S. W. Fanning, C. Fowler, Prof. G. L. Greene, The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637 USA; [c] Dr. C. G. Mayne, Prof E. Tajkhorshid, Beckman Institute for Advanced Science and Technology, The University of Illinois at Urbana‐Champaign, Urbana, IL 61801 USA [email protected] “Stapled” peptides are typically designed to replace two non‐interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl in the γ‐position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50 = 89 nM) replaces isoleucine 689 with an S‐‐methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nM). Through x‐ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S‐‐methyl peptide minimizes syn‐pentane interactions between α‐ and γ‐methyl groups. 142 Poster #96 Neuro‐imaging using Positron Emission Tomography a+
a+
Megan N. Stewart , Alexandra R. Sowa , Allen F Brooksb, and Peter J. H. Scott a,b* a
Interdepartmental Program in Medicinal Chemistry, bDepartment of Radiology. The University of Michigan, Ann Arbor, MI 48109, USA (+ these authors contributed equally to this work) [email protected] Positron Emission Tomography (PET) is a non‐invasive, in vivo imaging modality for the direct investigation of the appropriate drug target and subsequent action of the drug in living patients, but with less unwanted effects due to dosing below that required to elicit a pharmacological response. Transporters and receptors, such as the Dopamine D3 Receptor (D3R) and Gamma (γ)‐amino butyric acid (GABA) transporter 1 (GAT‐1), within the Central Nervous System (CNS) are implicated in a variety of neurological and subsequent neurodegenerative and psychiatric disorders, including schizophrenia, and Parkinson’s Disease. A complete understanding of the distribution, characterization, and pharmacology at these sites is yet to be fully explored. Herein we report progress on two projects exploring the synthesis and evaluation of novel radiolabeled (Fluorine‐18 or Carbon‐11) bioactive molecules selective for GAT‐1, and Dopamine D3R to better exploit them as a pharmacological target. 143 Poster #97 Discovery of a series of noncompetitive beta‐secretase (BACE1) inhibitors with the assistance of STD‐NMR Deyang Sun, Shuang Yang, Yujun He, Weishuo Fang* Institute of Materia Medica, Chinese Academy of Medical Sciences, 2A Nan Wei Road, Beijing 100050, China Abeta plays a central role in the Alzheimer’s disease (AD) pathogenesis and progression, and beta‐secretase (BACE1) is a rate limiting enzyme in the biosynthesis of Abeta. In the past 1‐2 decades, inhibitors targeting on BACE1 have been pursued extensively, based on the rationale that BACE1 inhibition may lead to the delay or even halt of AD progression rather than symptom‐modifying actions of currently available acetocholinesterase inhibition or GABA antagonism. Most of the potent BACE1 inhibitors discovered so far are active‐site directed competitive inhibitors with the possible detrimental effect through full inhibition of BACE1 functions, whereas a small portion of inhibitors are noncompetitive or with no definite mode of action1. Luteolin2 and p‐hydroxy‐cinnamic acid are two low to moderately active BACE1 inhibitors bound to different site of BACE1, based on our previous STD‐NMR study. Thus, a series of conjugates with the above two fragments with different linkers were designed, and it was indicated that both the atom composition and the length of linker influence BACE1 inhibitory activity. The inhibition kinetics of a representative conjugate was confirmed as non‐
competitive, and binding epitope analyzed by STD‐NMR. This series of sub‐micromolar active non‐competitive BACE1 inhibitors warrants further investigation as the alternative for the mainstream competitive inhibitors in the AD therapeutics expedition. OH
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1. Evin G, Barakat A. Degenerative Neurological & Neuromuscular Disease 2014,4:1‐19. 2. Choi S H, Hur J M, Yang E J, et al. Archives of Pharmacal Research 2008, 31(2):183‐7. 144 Poster #98 The Identification of (R)‐(2‐chloro‐3‐(trifluoromethyl)phenyl)(1‐(5‐fluoropyridin‐2‐yl)‐4‐
methyl‐6,7‐dihydro‐1H‐imidazo[4,5‐c]pyridin‐5(4H)‐yl)methanone (JNJ 54166060), a small molecule antagonist of the P2X7 receptor Devin M. Swanson*, Brad M. Savall, Kevin Coe, Freddy Schoetens, Tatiana Koudriakova, Jessica Wall, Jason Rech, Xiahou Deng, Meri De Angelis, Anita Everson, Brian Lord, Qi Wang, Hong Ao, Jason Rech, Brian Scott, Kia Sepassi, Timothy W. Lovenberg, Nicholas I. Carruthers, Anindya Bhattacharya, and Michael A. Letavic Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121 USA The synthesis and SAR of a series of 4,5,6,7‐tetrahydro‐imidazo[4,5‐c]pyridine P2X7 antagonists are described. Addressing speciation and microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7‐tetrahydro‐imidazo[4,5‐c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent human and rat P2X7 antagonist with an ED50 = 2.3 mg/kg in the rat, good pharmacokinetics across three species, acceptable safety margins in rat, and a predicted human dose of 100 mg QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism. 145 Poster #99 Quinoline Modulators of RORt Virginia Tanis, Maxwell Cummings, Aimee De Leon‐Tabaldo, Anne Fourie, Kristi Leonard, Rosa Luna, Rachel Nishimura, Hari Venkatesan, Craig Woods, Xiaohua Xue Janssen Pharmaceutical Research & Development [email protected] The IL‐23/Th‐17 pathway is important in the progression of autoimmune diseases, and biologics that inhibit the IL‐23/IL‐17 pathway demonstrate clinical efficacy in the treatment of psoriasis. Retinoic acid‐related orphan nuclear receptor gamma t (RORt) is a transcription factor that is a key regulator of Th17 cell differentiation and transcription of the genes encoding proinflammatory cytokines IL‐17A, F and IL‐22. Discovery of small molecule modulators of RORt would offer a unique opportunity for the treatment of autoimmune diseases such as psoriasis. A high‐throughput screen of RORt using ThermoFluor® technology identified a series of quinoline tertiary alcohols. Using a combination of structure‐based design and medicinal chemistry first principals we identified RORt modulators that possess good potency and physicochemical properties. The synthesis, SAR development, and optimization of ADME properties of compounds related to 1 will be presented. 1 146 Poster #100 Structural Requirements for Indolyl‐Pyridinyl‐Propenones to Induce Either Methuosis, Microtubule Disruption or Cytoplasmic Vacuolization Christopher J. Trabbic,† Jean H. Overmeyer,‡ William A. Maltese,*,‡ and Paul W. Erhardt*,† †
Center for Drug Design and Development, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH; ‡Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH *Corresponding authors: W.A.M ([email protected]); P.W.E. ([email protected]); presenting author: C.J.T. ([email protected]) Indolyl‐pyridinyl‐propenones (IPPs) confer a variety of biological activities, the most recognized being as anti‐cancer microtubule interacting agents. Our group has identified a form of non‐
apoptotic cell death termed ‘methuosis’ which is characterized by the accumulation of cytoplasmic vacuoles resulting in compromised membrane integrity and eventual cell death. Methuosis is triggered by certain IPP derivatives resulting from specific substitutions on the indole. Furthermore, structure‐activity relationship studies on a library of various IPP derivatives yielded unexpected results. Certain substitutions on IPP analogs induce methuosis in the low micromolar range. Other substitutions on the IPP scaffold can redirect the activity from methuosis to either cytoplasmic vacuolization (vacuoles present, no cytotoxicity) or microtubule disruption through the colchicine binding site. Substitutions that result in microtubule disruption demonstrated a significant increase in potency relative to the methuosis inducing compounds (Figure). Herein, we further describe the differential structural requirements to induce the various modes of biological activity. 147 Poster #101 Quinoline‐Based P2‐P4 Macrocyclic HCV NS3/4A Protease Inhibitors with pan‐
genotypic activity Francisco Velázquez,* Unmesh Shah, Charles Jayne, Samuel Chackalamannil, Zhuyan Guo, John Howe, Robert Chase, Aileen Soriano, Michael T. Rudd, John A. McCauley, Nigel J. Liverton, Joseph J. Romano, Kimberly J. Bush, Paul J. Coleman, Christiane Grisé‐
Bard, Marie‐Christine Brochu, Sylvie Charron, Virender Aulakh, Benoit Bachand, Patrick Beaulieu, Helmi Zaghdane, Sathesh Bhat, Yongxin Han, Joseph P. Vacca, Ian Davies, Srikanth Venkatraman. Merck Research Laboratories, Kenilworth, NJ 07033. United States of America. [email protected] A series of P2 – P4 macrocycles were identified by building on the profiles of previous lead compounds in our HCV NS3/4A inhibitor program. Development of the new class of compounds required broad enzymatic and cellular potency with emphasis on genotype‐3a and clinically relevant mutants. Structural modeling studies allowed the identification of suitable positions in the P2‐biaryl ring system of lead compounds to append amine containing groups to improve potency profiles and modulate physicochemical properties. These studies led to identification of compounds which displayed excellent potency across different genotypes (gt‐3a IC50 ≤ 3 nM). 148 Poster #102 Pyridopyrimidinone‐Core Subseries as Highly Selective and Brain‐Penetrant Alternative to GNE‐0723, a GluN2A‐Selective NMDA Receptor Positive Allosteric Modulators (PAMs) Elisia Villemure* ([email protected]), Matthew Volgraf*, Benjamin D. Sellers*, Yu Jiang†, Cuong Q. Ly*, Po‐wai Yuen†, Guosheng Wu, Aijun Liu†, Patrick J. Lupardus*, Heidi Wallweber*, Bianca M. Liederer*, Gauri Deshmukh*, Jesse E. Hanson*, David H. Hackos*, Kimberly Scearce‐Levie*, Jacob Schwarz* *
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States; †Pharmaron‐
Beijing, 6 Taihe Rd, BDA, Beijing 100176, PR China The N‐Methyl‐D‐Aspartate receptor (NMDAR) is a Na+‐and Ca2+‐permeable ionotropic glutamate receptor that is activated by the co‐agonists glycine and glutamate. NMDARs are thought to be involved in learning and memory, and their dysfunction has been implicated in a number of neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer’s disease. Towards this end, NMDARs have long been targets of pharmacological modulation, most notably in the form of non‐selective (i.e., memantine and ketamine) and subunit‐selective (i.e., ifenprodil) antagonists. More recently, the identification of NMDAR positive allosteric modulators (PAMs) have appeared in the literature with the aim of targeting neural circuit dysfunction via both non‐selective and subunit‐selective (i.e., GluN2C/2D) PAMs. Herein we describe the discovery of potent GluN2A‐selective NMDAR PAMs starting from a high‐throughput screening hit. Using structure‐based design we sought to increase potency at the GluN2A subtype, while improving selectivity against related AMPA receptors and other GluN2 subtypes. 149 Poster #103 Crystal structures of large, multi‐domain, catalytically active KDM5a fragments reveal inhibitor mechanism of selective drug CPI‐455 Maia Vinogradova1, Victor Gehling2, Amy Gustafson1, Shipli Arora2, Yichin Liu1, E. Megan Flynn1, Andrea G. Cochran1, Richard T. Cummings2, Brian K. Albrecht2, Jean‐Christophe Harmange2, Patrick Trojer2, Marie Classon1, and James R. Kiefer1 1
2
Genentech, Constellation Pharmaceuticals [email protected] Histone demethylase KDM5a modulates chromatin structure by removing methylation marks from lysine 4 of histone 3. Knockdown of KDM5a in cancer cell lines was shown to reduce the number of cells surviving anti‐tumor drug treatment. We designed a catalytically active fragment spanning the N‐terminal half of the protein and determined its crystal structure at 3.2 Å resolution. The contiguous construct of KDM5a and the analogous construct with internal deletion of PHD1 domain appeared to have identical fold and similar catalytic activity. We discovered the selective inhibitor of KDM5a, CPI‐455 (IC50=10 nM), in a medicinal chemistry campaign following a high throughput screen. The structures of KDM5a revealed a 2‐OG competitive mode of binding of CPI‐455 and the structural basis for its selectivity. The structure of KDM5a, the largest “intact” multi‐domain demethylase structure available to date, allowed us to model this enzyme on the nucleosome, suggested a mode for histone tail binding. 150 Poster #104 Design and characterization of thiol modified 5‐methylcytosine containing oligonucleotide: A potential Z‐DNA forming probe Kulwadee Sawaspaiboontawee1,2, Bodin Tuesuwan1,2, Gota Kawai3, and Vorasit Vongsutilers1,2 * 1
Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; 2Medicinal and Analytical Pharmaceutical Chemistry Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; 3Department of Life and Environmental Sciences, Faculty of Engineering, Chiba Institute of Technology, Chiba, Japan [email protected] Discovery of Z‐DNA binding proteins has ignited the interest in search for Z‐DNA functions. The interaction between Z‐DNA and Z‐DNA binding proteins is the key to understand biological role of Z‐DNA. Biosensor with Z‐DNA forming probe can be useful to study the interaction between Z‐DNA conformation and Z‐DNA binding proteins. The pivotal step of Z‐DNA biosensor development is the design of oligonucleotide probe that can overcome Z‐DNA conformational strain and convert to the left‐handed polymorph. In this study, the 5’‐thiol oligonucleotide which contains an alternating 5‐methylcytosine‐guanine residue was designed and developed as Z‐DNA forming probe. The capability of the designed probe to form Z‐DNA and bind to Z‐DNA specific binding protein were investigated with circular dichroism. The result demonstrated the 5‐methylcytosine on Z‐DNA forming probe has facilitated the formation of Z form which enables the designed probe to bind with Z‐DNA antibody. The Z‐DNA forming characteristic from this preliminary study indicates suitability of the designed probe to be used for Z‐DNA‐
based biosensor development. Keywords: Z‐DNA, Z‐DNA forming probe, 5‐methylcytosine, circular dichroism, biosensor 151 Poster #105 Development and Structural Evaluation of Potent and Selective G‐protein Coupled Receptor Kinase 2 Inhibitors Helen V. Waldschmidta,b,*, Kristoff T. Homanb,d, Osvaldo Cruzb,c,d, Marilyn C. Catob,d, Jessica Waninger‐Saronib,d,e, Alessandro Cannovof, Jianliang Songf, Joseph Y. Cheungf, Walter J. Kochf, John J. G. Tesmerb,d, and Scott D. Larsena Vahlteich Medicinal Chemistry Core, College of Pharmacy, bLife Sciences Institute, cPhD Program in Chemical Biology, dDepartments of Pharmacology and Biological Chemistry, e
Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, 48109, fCenter for Translational Medicine, Temple University, Philadelphia, Pennsylvania, 19140 a
In the failing heart the sympathetic nervous system (SNS) elevates catecholamine levels leading to stimulation of the β‐adrenergic receptors (βars). Due to this increased signaling the βars become overstimulated resulting in desensitization via G‐protein coupled receptor kinases (GRKs) and severe uncoupling. Specifically, GRK2 is elevated in heart failure and inhibition of GRK2 interrupts the internalization of the βars allowing the heart to regain stimulation from the SNS. Our lab identified a small molecule inhibitor of GRK2: GSK180736A, a known Rho‐
associated coiled‐coiled kinase inhibitor. Utilizing the structural motifs in combination with the previously reported potent and selective GRK2 inhibitor Takeda103A a library of hybrid inhibitors was designed and synthesized. This campaign produced several compounds with impressive potency and selectivity for GRK2 over other AGC kinases. The most selective inhibitor was CCG224406, with an IC50 for GRK2 of 130 nM, >700‐fold selectivity vs other GRK subfamilies, and >150‐fold selectivity over ROCK1. Crystallization of these inhibitors with GRK2 and GRK5 has allowed for further development and rationalization of the mechanism of selectivity among the GRK subfamilies and other AGC kinases. 152 Poster #106 Discovery and Optimization of Quinoxaline‐pyrrolodihydropiperidinones as Potent Pim‐1/2 Kinase Inhibitors Hui‐Ling Wang, Victor J. Cee, Frank Chavez, Jr., Bradley Herberich, Brian A. Lanman, Liping H. Pettus, Anthony B. Reed, Bin Wu, Ryan P. Wurz, Kristin L. Andrews, Jie Chen, Dean Hickman, Xin Huang, Jimmy Laszlo, III, Matthew R. Lee, Nadia Guerrero, Bethany K. Mattson, Yen Nguyen, Christopher Mohr, Karen Rex, Christine E. Sastri, Paul Wang, Qiong Wu, Tian Wu, Yang Xu, Yihong Zhou, Jeffrey T. Winston, J. Russell Lipford, and Andrew S. Tasker Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320‐1799, United States Pim‐1, ‐2, and ‐3 are highly homologous and constitutively active serine/threonine kinases. The three Pim isoforms phosphorylate a diverse group of proteins with known roles in proliferation, survival, apoptosis, and differentiation. In human disease, high expression of the three Pims has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. A high‐throughput screen of our compound collection identified a hit composed of a 1,5‐naphthyridine connected to a 6,7‐dihydro‐1H‐pyrrolo[3,2‐c]pyridin‐4(5H)‐one. A hit‐to‐lead optimization campaign resulted in the identification of improved inhibitors with a quinoxaline core. The structure‐
activity relationships of quinoxalines will be described. Finally, the preclinical characterization of the lead molecules and their potential use for treatment of Pim‐driven malignancies will be presented. 153 Poster #108 Discovery and Optimization of Chitinase Inhibitors Libo Xu, Amy K. Farthing, James F. Dropinski, Guo Q. Shi, Peter T. Meinke, Giovani Scapin, Kalpit Vora, Joe Menetski, Gene Porter, Julie DeMartino and Kun Liu Merck Research Labs, Rahway, NJ 07065 Chitin is a naturally occuring polysaccharide found in the cell walls of fungi, in the exoskeletons of crustaceans and insects, and in the microfilarial sheaths of parasitic nematodes. Pathogens use hydrolytic chitinases to protect themselves from the harsh conditions inside the animal or plant host and therefore chitinase inhibitors have received attention as new biopesticides and microbial biocontrol agents. Of the known chitinase inhibitors, allosamidin and its derivatives are the most prominent and best characterized inhibitors to date. Although mammals do not express chitin synthase genes, several human chitinases have been identified, including chitotriosidase and acidic mammalian chitinase (AMCase). The biological importance of these proteins are poorly understood, though AMCase may play a role in asthma pathogenesis. We believe novel chitinase inhibitors could be important tool compounds to help further the understanding of the biological and pathological functions of chitinase, and while also having the potential to be therapeutics for the prevention and/or treatment of asthma. Through a hit finding effort, we discovered a lead that inhibited both AMCase (IC50 200 nM) and chitotriosidase (IC50 200 nM). The potency of this lead was significantly enhanced via structure‐
activity relationship (SAR) optimization that was guided by X‐ray crystallography. The SAR investigations that led to the discovery of a very potent inhibitor (AMCase IC50 4 nM, chitotriosidase IC50 17 nM) will be presented. 154 Poster #109 Covalent inhibitors of the bacterial glycosyltransferase LgtC Yong Xu,1 Ruth Smith2 & Gerd K. Wagner1* 1
King’s College London, Department of Chemistry, Britannia House, 7 Trinity Street, London, SE1 1DB, UK; 2King’s College London, Institute of Pharmaceutical Science, Franklin‐Wilkins Building, London SE1 9NH, UK [email protected] The presence of digalactoside structures in the lipooligosaccharide coat increases the serum resistance of Gram negative pathogens such as Neisseria and Haemophilus. The biosynthesis of these digalactosides requires the transfer of D‐galactose from UDP‐galactose to a terminal lactose acceptor, which is catalyzed by the retaining galactosyltransferase LgtC. Inhibition of LgtC may therefore be a promising strategy for the discovery of new anti‐virulence agents. Only a limited number of LgtC inhibitors have been reported to date. We have identified a novel small molecular inhibitor chemotype for LgtC with low micromolar inhibitory activity. Various experiments indicate that the inhibitors bind irreversibly to a non‐catalytic cysteine residue in the acceptor binding site. This is the first example for this type of covalent inhibition in the GT family. Analysis of other GT structures and sequences suggests that this new inhibition mode has broad application in the design of potent inhibitors against other bacterial GTs. 155 Poster #110 Benzimidazole analogs target Methicillin Resistant Staphylococcus aureus and inhibit WTA biosynthesis Shu‐Wei Yang1, Jianping Pan1, Christine Yang1, Marc Labroli1, Weidong Pan1, John Caldwell1, Jing Su1, Sookhee Ha2, Sandra Koseoglu3, JingChen Xiao3, Payal Sheth3, Charles G. Garlisi3, Sang Ho Lee4, Hao Wang4, Christopher Tan4, Terry Roemer4 1
Discovery Chemistry, Merck Research Laboratories (MRL), Merck & Co., Inc., Kenilworth, New Jersey, United States; 2Structural Chemistry, MRL, Merck & Co., Inc., Kenilworth, New Jersey, United States; 3In Vitro Pharmacology, MRL, Merck & Co., Inc., Kenilworth, New Jersey, United States; 4Department of Infectious Disease, MRL, Merck & Co., Inc., Kenilworth, New Jersey, United States shu‐[email protected] Multidrug resistant bacteria pose a serious threat to global human health. These organisms, such as MRSA, are widely resistant to ‐lactams, perhaps our most important class of antibiotics. Accordingly, new antibiotics displaying novel mechanisms of action are urgently needed. Wall teichoic acids (WTA) are present in the G(+) bacterial cell wall, extending outside of the peptidoglycan (PG) layer, and are attached to PG. WTA functionally, contributes to cell morphology, division, virulence, and antibiotic resistance. Consequently, WTA biosynthesis provides an important new target for antibacterial drug discovery. Here we describe a novel series of synthetic inhibitors targeting TarO, the first enzyme involved in WTA biogenesis. Importantly, this benzimidazole‐based series displays potent potentiation of ‐lactams against MRSA both in vitro as well as in a murine infection model. The structure‐activity relationship of the benzimidazole series will be described. 156 Poster #111 Identification and optimization of potent, selective and cellularly‐active KDM5 inhibitors Birong Zhang1, Jun Liang1, Sharada Labadie1, Dan Ortwine1, Maia Vinogradova1, Jim Kiefer1, Victor Gehling2, Steve Bellon2, JC Harmange2, Richard Cummings2, Yves Leblanc2, Shobu Odate2, Shane Buker2, Fei Lan2, Peter Sandy2, Louise Bergron2, Brian K. Albrecht2, Chris Bailey2, Tommy Lai3, Jiangpeng Liao3, Xiaoping Zheng3, Yichin Liu1, Amy Gustafson1, Erica Van der Porten1, Winfred Mao3, Bianca Liederer1, Gauri Deshmukh1, Maries Classon1, Patrick Trojer2, Pete Dragovich1, Lesley Murray1 1
Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA; 2Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA; 3Wuxi Apptec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131, China [email protected] KDM5 enzymes play critical roles in removing the methyl group(s) from histone H3K4Me3. A diversity screen against KDM4C led to identification of Compound 1 with sub‐micromolar KDM5A potency and approximately 10‐fold selectivity against KDM4C. Compound 1 was optimized to afford Compound 2, a 10 nM inhibitor of KDM5A, and highly selective against other KDMs. Compound 2 was further optimized through structure‐ and property‐based design to afford Compound 3 with improved KDM5 cellular potency and excellent mouse PK profile, providing a robust chemical probe for studying KDM5 biological function in vivo. 157 th
The 35 National Medicinal Chemistry Symposium June 26‐29, 2016 Chicago, IL USA Palmer House Hilton 17 East Monroe Street Chicago, Illinois 60603 USA +1‐312‐726‐7500 158