Drug Discovery Pipeline Brief Report 2011

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Drug Discovery Pipeline
Brief Report
2011
Executive Summary
The Drug Discovery Pipeline (DDP) was established in 2009 at the Guangzhou
Institutes of Biomedicine and Health (GIBH). The mission of the DDP is to capture the
best ideas developed within GIBH and translate those ideas into drug discovery projects.
Prior to the creation of the DDP, there was no mechanism in place to transform
concepts into drug discovery projects. However, after the formation of the DDP, GIBH
now has the required expertise, platform technologies, centralization and necessary
integration of disciplines to enable effective drug discovery research, which is not found
at most institutes in China.
Since its inception the DDP has achieved five important milestones, which
include: (1) Centralization of key technology groups to support drug development; (2)
Integration of project teams to enable the advancement of drugs; (3) Development of a
sustainable pipeline of projects with novel intellectual property (IP); (4) Establishment of
key international partnership for the co-development of drugs; and (5) Creation of new
companies in Guangzhou using IP matured in the Pipeline. A 6th milestone, which
includes advancing a new drug into clinical trials, is expected to be achieved in late 2012
/early 2013.
I. Centralizing the key technology groups
In order to effectively develop drugs at GIBH, it was necessary to first create and
centralize several technology groups including High Throughput-Screening (HTS),
Structural Biology, Pharmacokinetics (PK), Biomarkers, Medicinal Chemistry and BioTherapeutics. All of these groups have been established and are led by experienced
senior scientists, many of who have strong drug discovery experience (Figure 1).
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Figure 1: Structure of DDP
Micky Tortorella
(CTO)
Administration
3 FTE*
Chemistry
Biology
(Donghai Wu)
(Zhengchao Tu)
PK/ADME
(Xiaorong Liu)
Structure
(Jinsong Liu)
Biomarkers
(Scott Spillman)
18 RA*
11 RA
5 RA
9 RA
1 RA
2 RA
*FTE=Full Time Employee
•
HTS
(Ding Ke)
BioTherapeutics
(Daiguan Yu)
2 RA
RA=Research Associate
HTS – This team is capable of screening thousands of compounds per week in various
enzyme and cell based assays at a low price using new automated robotic equipment
purchased in 2010. At this time the group has screened several thousand compounds
and identified lead molecules for several drug discovery projects at GIBH in the areas of
cancer, inflammation and infection (Table 1).
Table 1: Productivity of High Throughput Screening.
Targets（Related diseases）
Protein Kinases
ABL (CML)
ABL (T315I) (CML)
Abl（E255K）(CML)
ABl（G250E）(CML)
Abl（Y253F）(CML)
ABl（Q252H）(CML)
ABl（H396P）(CML)
ABl（M351T）(CML)
ALK（Cancer）
Kit (GIST) (Cancer)
EGFR (Breast and lung cancer)
Progress Report
Hits identified
351
351
231
231
231
231
231
231
5
231
347
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EGFR (T790M) (Breast cancer)
EGFR（L858R）(Breast and lung cancer)
EGFR（T790M&L868R）(Breast cancer)
EGFR（L861Q）(Breast and lung cancer)
Her2 (Breast cancer)
AKT1（Cancer）
AKT2 （Cancer）
AKT3 （Cancer）
Proteases
DPPIV (Diabetes)
DPP8 (Diabetes)
DPP9 (Diabetes)
NS3/4A (HCV)
Furin （virous infection）
Other molucular targets
Neuraminidase S (Influenza)
Neuraminidase S (Influenza)
COX-1（Inflammation and RA）
COX-2（Inflammation and RA）
HDAC1（Cancer）
HDAC7 （Cancer）
Cell-based infectious diseases
Influenza
Ev71(Enterovirus infection)
347
305
305
305
84
35
35
35
50
17
38
1
1
32
32
1
1
15
15
62
1
•
Structural Biology – The group is currently supporting the lead optimization of
compounds for several drug discovery projects. The support they provide to the DDP
include the expression of protein, crystallography, computer-aided drug design and
high-throughput virtual screening. The team recently developed a new super computer
platform, capable of virtually screening ~40M compounds per target. The team is
enabling the design of inhibitors targeting ADAMTS4/5, p38 alpha, beta, delta, gamma,
cKIT/AKT1/EGFR, Plasmepsin II/IV/V and G1B.
•
Pharmacokinetics/ADME – The team provides data regarding the drug metabolism,
pharmacokinetics and acute safety of our lead compounds. These data are critical for
the prioritization and development of new pharmaceutical drugs at GIBH. Currently the
capabilities of the team include standard pharmacokinetics, blood brain barrier
penetration, acute toxicity in rodents, metabolic stability of compounds, plasma protein
binding of drugs, drug-drug interactions, Caco2 and Zebra fish toxicity. The team has
analyzed over 100 compounds for the DDP, allowing the project teams to optimize and
advance lead molecules in a timely manner.
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Table 2: Productivity of Pharmacokinetics
Analysis
Number of
Compounds Tested
Pharmacokinetics
85
CNS penetration
7
Acute toxicity
10
Metabolic stability
35
Protein binding
28
Caco2
21
Drug drug interaction
81
Zebra Fish (Toxicity)
16
Rat air pouch inflammation
model
Drug toxicity in rat
2
Human hepatocyte culture
2
4
•
Biomarkers - In collaboration with Plexera, novel biomarker based chips for rapid
detection of thousands of proteins in the blood are being developed. The chips will be
used as diagnostics to determine the safety and efficacy of our lead candidate drugs by
monitoring the modulation of selected biomarkers in bodily fluids such as urine, synovial
fluid and plasma. At this time the team has identified novel chip surfaces to reduce
background and chip to chip variation .
•
Medicinal Chemistry – The newly integrated chemistry team has and is currently
designing novel drugs in several different therapeutic indications. The group has made
several hundred proprietary compounds targeting pathways in cancer, inflammation,
infection, arthritis and metabolic diseases.
Table 3: Productivity of Medicinal Chemistry
Project/Traget
Cancer
Arthritis
Alzheimer’s
Diabetes
Flu
Malaria
Pain
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Number of
compounds made
300
100
200
100
120
6
6
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•
BioTherapeutics – Protein based therapeutics with an ephasis on proteases are
currently being developed for the treatment of various blood disorders. Proteases are
naturally occurring peptide-cleaving enzymes that regulate a wide variety of biological
functions. In the DDP we are using the potential of these enzymes as bio-therapeutics by
directing them to cleave specific proteins in the blood that promote health. Unlike
standard drugs, a single proteinase molecule can inactivate or activate thousands of
target molecules, resulting in higher efficacy and lower dosing regimens compared to
small molecules or antibodies. Currently, the team is expressing a more active species of
ADAMTS-13 for the tratment of thrombocyopenic disorders.
II. Integration of project teams to enable the advancement of drugs
To effectively enable drug development at GIBH, the DDP has been organized
using a very different model that is not traditionally found at other institutes in China.
In the DDP, there are no individual principle investigators (PIs) working in isolation. In
contrast, all senior staff and corresponding reseacrh associates work in teams
supporting specific projects that are deemed high priority. The DDP operates under a
“Project” rather than “PI” centric system. The integration of medicinal chemistry and
biology has been successful and current project teams are able to provide the critical
mass and expertise needed to advance drugs and cultivate new intellectual property
(Figure 2).
Figure 2: Model of the “Project Centric” system employed in the DDP
Project
Chemistry
Leader
Biology Leader
Team Members
Protein
Screening
Enzymology
Biomarker
validation
Animal models
PK/ADME
Safety
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Team Members
Molecule design
Synthesis
Purity
Crystallography
Scale-up
Formulations
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III. Development of a sustainable pipeline of projects with novel intellectual property
After only one and a half years after its inception, the DDP has cultivated a
porfolio of drug targets that enjoy strong intellectual property. Current programs are
developing drugs to treat Alzheimer's disease, leukemia, inflammation and infectious
diseases. Two projects are at candidate selection, one project is at lead optimization,
three projects are at hit identification and several projects are at early exploration
(Table 4).
Table 4: Pipeline of projects and estimated time to IND filing.
Disease
Leukeumia
Alzheimer's
Target
Mutant forms of
the Bcr-Abl
Kinase
Neural
Inflammation
Aggrecanase
Stage
Candidate
Selection
Joint
Inflammation
Inflammatory
Genes
Candidate
Selection
Lead
Optimization
Lead
Optimization
Malaria
Plasmepsin V
Hit Identification
Osteoarthritis
Thrombocyopenic
Disorders
Pain and Cancer
ADAMTS-13
Early Exploration
(Protein Therapy)
COX-2
Hit Identification
IP
Compound,
D824, a new
kinase inhibitor
Compound,
HWH-2-130
Carboxylate
inhibitors
AS001:
siRNA/Particle
conjugate
New aspartyl
protease
inhibitors
ADAMTS-13
protein
constructs
Novel chromene
inhibitors
Time to IND
2012
(Oral, Small Molecule)
2012
(Oral, Small Molecule)
TBD
(Oral, Small Molecule)
2013
(Local Injectable)
TBD
(Oral, Small Molecule)
TBD
(Protein, IV)
TBD
(Oral, Small Molecule)
*TBD = To Be Determined
Summary of DDP projects expected for IND filing in 2012/13
1. Research and Development of a New Drug for the Treatment of Drug-Resistant
Leukemia (Project Leader is Dr. Ding Ke)
Background and Medical Need: Chronic myelogenous leukemia (CML) has a
high mortality rate of 20%-30%, two years after a confirmed diagnosis. Approximate 25%
of patients with CML die every year and the average survival time is just 3 to 5 years.
The age of onset ranges from 20 to 50 and in China, there are 30,000 new cases
diagnosed each year. Gleevec therapy alone can alleviate the condition in many patients
suffering from CML. However, because of extensive usage of Gleevec, it is becoming
less effective. Some CML patients are inherently resistant to Gleevec, and some
respond to Gleevec in the beginning, but acquire secondary resistance over the course
of the treatment.
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Rationale for the Approach: The major cause of resistance to Gleevec is a
secondary mutation in the kinase domain of target gene expression products. Research
indicates that the common point mutation sites related to Gleevec resistance include
E255K, E255V, T315I and D276G of Bcr-Abl and D816 of c-KIT. The Bcr/Abl, T315I
mutation, one of the obstinate drug-resistant mutations is the most common mutation,
representing about 20-30% of all cases. The clinical drug resistance mediated by the
T315I mutation of Bcr-Abl remains a significant medical problem and at this time there
are no drugs targeting the T315I point mutation on the market. As a result, it is urgent
to develop novel drugs for the treatment of this type of drug-resistant leukemia.
Validation of Lead Chemistry: Using the principles of rational and computeraided drug design, the project team has successfully designed and synthesized a series
of leading compounds with strong intellectual property. In vitro data show that the
novel compound, D824 has an activity 1000 times more potent than Gleevec on chronic
myloid leukemia cells containing no mutations, but more importantly exhibits excellent
activities on all cell lines that are resistant to Gleevec treatment. This series of
compounds has excellent activities against the T315I mutation found in the Bcr-Abl
kinase active site, which cannot be treated with current drugs. Domestic and
international data report that neither the first-line drug Gleevec or the second-line
drugs Dasatinib or Nilotinib (approved by FDA for the treatment of CML) are effective in
patients with the T315I mutation, because their IC50 values all exceed > 50 µM. The IC50
of D824 is <10 nM and its activity is 5,000 times more active than current clinical
therapeutic drugs. D824 was found to be efficacious in a rodent model of leukemia as
well as models that measure solid tumors. Toxicity and pharmacokinetic experiments
indicate that D824 has a reasonable safety index with excellent pharmacokinetic
properties such as oral bioavailability and a very lon half-life, all within range for the
requirements of a new drug.
2. Research and Development of a New Drug for the Treatment of Alzheimer's Disease
(Project Leaders are Wenhui Hu and Donghai Wu)
Background and Medical Need: Alzheimer’s disease (AD) is a major health and
societal problem. It is extremely costly to the patients, their families and to society as a
whole. In 2007, it was estimated that $100 billon was spent in the United States on
health care expenses and lost wages for AD patients and their caregivers. Further
estimates predict that $375 billion will be spent annually by 2050. Unfortunately, AD
drug discovery has been disappointing as no disease modifying drugs are available.
Current drugs used to treat AD only treat the symptoms of the disease.
Rationale for the Approach: Alzheimer’s disease is characterized pathologically
by the deposition of amyloid fibrils and neurofibrillary tangles in the brain. Many
biochemical and genetic evidence heavily favors the “amyloid-β hypothesis” (Figure 3) .
However, new data suggest that neuroinflammaiton may play a bigger role than
previously thought in the development of the disease. The goal of the DDP is to
advance inhibitors that block neuroinflammation as a means for attenuating the
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progression of AD. Minozac, discovered by Dr. Wenhui Hu was one of the first drug
candidates designed for blocking neuroinflammation, representing a new class of
compounds for the treatment of Alzheimer’s disease. Recently, his team has discovered
several new and highly potent inhibitors of neural inflammation with superior
properties compared to the original lead molecule, Minozac.
Validation of Lead Chemistry: The new series of compounds are thousands of
times more potent than Minozac in variuos cell based assays of neural inflammation.
The compounds are drug-like candidates as they possess excellent PK properties
without apparent acute toxicity in rodents (safety index up to 1000x the efficaious dose).
In addition, lead compound, HWH-2-130 has demostrated significant efficacy in several
in vivo models of Alzheimers disease , stroke and rheaumatoid arthritis. IND filing is
anticipated in 2012 pending chronic safety evaluation.
Figure 3: Model of neural inflammation in AD.
3. Research and Development of Anti-Osteoarthritis and Anti-Rheumatoid Arthritis
siRNA Drugs (Project Leader is Dr. Biliang Zhang)
Background and Medical Need: Osteoarthritis (OA) is one of the leading causes
of disability in the world, with more than 10% of the elderly population having
symptomatic disease. Rheumatoid arthritis (RA) is a chronic, inflammatory disease that
affects approximately 0.5 to 1 percent of adults worldwide and commonly results in
joint destruction and significant impairment in the quality of life. Many pathogenic
pathways of OA and RA have been revealed recently, which led to development of
various novel therapies. During the past 20 years, most of the development of new
therapies is in disease-modifying anti-rheumatic drugs (DMARDs) and disease modifying
osteoarthritic drugs (DMOADs), especially biological DMARDs. With the discovery of
new pathways and the application of drug delivery strategies, more growth is
anticipated in this therapeutic field. Thus, significant opportunity exists for agents such
as siRNAs that can stop or reverse disease progression and act as disease-modifying
agents.
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The current treatments of RA include 4 categories: non-steroidal antiinflammatory drugs (NSAIDs), glucocorticoids, non-biologic disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs. Till date, the pharmaceutical industry
has failed to bring effective and safe disease modifying osteoarthritic drugs (DMOADs)
to the millions of patients suffering from this serious and deliberating disease. RNA
interference (RNAi) is a revolutionary discovery in life science and has become a
powerful tool for studying the gene function, which mediates gene inactivation in
organisms, mammalian cells and even animals. RNAi technology has the potential to
create new therapies in humans including anti-OA and RA therapies. In this project, we
are developing novel slow-releasing siRNA drugs as anti-OA and RA therapies.
Rationale for the Approach: RNA interference has not only become a standard
method of molecular biology—it has already made its way into the clinic. Around a
dozen clinical studies based on RNAi are curently in progress and the initial results are
promising. RNAi technology can be used against any disease in which a deleterious gene
is over-expressed (for example, cancer, viral infections, inflammation). The advantage of
employing RNAi in drug discovery is speed; progressing from target identification to preclinical evaluation can occur in as little as 6 to 9 months. However, the delivery of the
siRNAs into cells presents one of the greatest challenges in the development of new
RNAi therapies. The goal of this project is to develop a universal formulation for
delivering anti-arthritic siRNAs locally via intra-articular injection into the joints of
patients. Since articular cartilage and the surrounding synovial fluid (SF) is highly
negatively charged, a formulation employing postively charged nano-partciles maybe an
effective strategy for delivering anti-arthritic siRNAs selectively to the diseeased joints
for a sustained period of time after only a single injection.
Validated siRNA Targets and Delivery Formulation: A series of siRNAs have been
made targeting key genes implicated in both osteoarthritis and rheumatoid arthritis
including TNFα, ADAM-17, ADAMTS-5, PACE4, JAK3, CD44, CD36, NF-kB and RHAAM.
The active siRNAs were screened against each gene in vitro. The IC50 has been
determined for each individual active siRNA using synovial fibroblasts. The most active
siRNA showed an IC50 as low as 10 pM. A proprietary formulation that uses positively
charged particles to deliver the oligonucleotides has been identified. The major
components of the formulation is a co-polymer with a low molecular weight polycation
and a biodegradable polymer. The positively charged co-polymer can form nanoplexes
or nanoparticles with siRNAs and these nanoplexed-siRNAs can effectively penetrate
into synovial fibroblasts and supress the expression of inflammatory genes implicated in
both OA and RA (Figure 4). IND filing is anticipated in 2013 pending chronic safety
evaluation.
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Figure 4: Bio-surgery concept for the treatment of inflammatory arthritis.
IV. Establishment of key international partnership for the co-development of drugs
In order to enhance the drug discovery efforts at GIBH, the DDP has established
several international partnerships with premier scientists and institutions in the United
States with the mission of co-developing drugs. Our international partners offer
experience and innovation in drug discovery. In addition, these collaborations allow
GIBH to share the risk and expenses associated with drug development. Currently, GIBH
has two external partnerships with (1) The Center for World Health & Medicine at Saint
Louis University to develop anti-malaria therapies and (2) Legacy Pfizer scientists to
advance novel chromene based inhibitors of COX-2 that spare both the renal and
cardiovascular risks associated with current celecoxibs (Figure 5).
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Plasmepsin V
Inhibitors for
Malaria
3rd Gen. COX-2
Inhibitors for Dental
Pain and Cancer
The Center for
World Health &
Medicine, Saint
Louis University
Legacy Pfizer
Scientists
GIBH
GIBH
Washington
University
Figure 5: External partnerships at GIBH
1. Inhibitors of Plasmepsin V as Novel Anti-Malarial Agents (Project Leaders at
GIBH are Xiaoping Chen and Ding Ke)
Project Summary and Proposal
Each year there are approximately 350-500 million cases of malaria, killing
between one and three million people, the majority of whom are young children in subSaharan Africa, where ninety percent of malaria-related deaths occur. Although there
are a number of drugs used to treat malaria, resistance to these drugs is becoming more
widespread. Thus, therapies targeting novel modes of action are greatly needed. One
promising new antimalarial target is the Plasmodium specific aspartyl protease,
Plasmepsin V (PMV), recently discovered to be the key gate keeping protease
responsible for the cleavage and translocation of several hundred PEXEL-containing
proteins destined for export into the host erythrocyte. PMV and many of these
downstream PEXEL-containing export proteins are essential for the survival of the
parasite (Figure 6). The aim of this project is to identify potent inhibitors of PMV and
demonstrate their therapeutic value for the treatment of malaria.
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Figure 6: Life cycle of P. falciparum
Project Progress
HIV-1 aspartyl protease inhibitors lopinavir, ritonavir, saquinavir, and nelfinavir
have been demonstrated to be weak inhibitors of PMV (~15-100 µM). This is not
surprising, given the distant homology of PMV to other aspartyl proteases such as βsecretase and similarities between the PEXEL sequence in substrates for PMV and
protein substrates of HIV-1 aspartyl protease. However, with molecular weights
exceeding 700 and weak potencies, these HIV protease inhibitors are not good starting
points for optimization towards an anti-malarial drug. Our approach to identifying a
more suitable starting point for optimization involves screening collections of aspartyl
protease inhibitors to be secured from commercial, literature, pharmaceutical donors,
and our internal medicinal chemistry program . Recently a set of BACE-1 inhibitors has
been identified as active agents against PMV and are being used as starting points for
further optimization.
The Center for World Health & Medicine, Saint Louis University (www.cwhm.org)
The CWHM is a non-profit group whose expertise is the translation of basic
science into the discovery and development of novel drugs for rare and neglected
diseases. The CWHM consists of a highly skilled and successful team of former Pfizer
drug discovery scientists. The scientists on this team have expertise at high throughput
protease assay development, drug design and medicinal chemistry, in vivo
pharmacology and pharmacokinetics, and preclinical development.
2. Chromene COX-2 Inhibitor Project (Project Leader at GIBH is Yanmei Zhang)
Project Summary and Proposal
The chromene pharmacophore represents a novel drug class of COX-2-selective
inhibitors (coxibs) that have a carboxylate moiety and do not bind in the hydrophobic
binding pocket of the COX-2 active site. As a class, they have been shown to confer
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potency, efficacy, and selectivity on par with the diaryl heterocyclic coxibs (eg, celecoxib,
valdecoxib, rofecoxib, and etoricoxib) in the standard rat models of inflammation and
pain. The chromene coxib clinical candidate, SC-75416, was shown to be differentiated
from the diaryl heterocyclic coxibs in that it conferred reduced tactile allodynia in a rat
model of neurophathic pain. A testing scheme has been implemented and the synthesis
of novel and potentially superior chromene coxib analogs has been initiated. The
chromene pharmacophore may prove to provide advantages over the existing coxibs for
the treatment of inflammation and pain, especially for those patients who are
inadequately served by the analgesic medications available today. As a class, the
chromene coxibs have the potential to be renal-sparing and thereby mitigate coxibinduced hypertension due to their intrinsic and distinct structural, pharmacological, and
physiochemical properties. These combined properties, if borne out, could allow
Chinese sFDA approval, as well as world-wide approval, including the United States, with
first-in-class and best-in-class status.
The overall goal is to (1) identify novel and potentially superior chromene coxibs
for the treatment of acute and chronic pain/inflammation and, possibly, cancer. (2) The
initial goal is to identify a chromene coxib clinical candidate within 18 months for the
treatment of acute dental pain in China. Acute dosing (i.e., ≤7 days) will be targeted
initially in order to avoid the cardiovascular side effects (i.e., hypertension, edema,
myocardial infarction, and stroke) associated with chronic dosing of some coxibs (e.g.,
rofecoxib). (3) In parallel, the renal- and hypertension-sparing properties of the lead
chromene coxibs will be evaluated. (4) Chronic indications of pain and inflammation
(e.g., OA and RA) in China will be explored if the clinical chromene coxib candidate is
renal- and hypertension-sparing.
Project Status
A testing scheme has been implemented to identify novel and potentially
superior chromene coxib analogs. The chromene analogs, SC-75416 (R/S), 29b (R/S),
and 34b (R/S), and celecoxib are being synthesized as comparator coxibs. The synthesis
of novel and potentially superior chromene coxib analogs has been initiated.
Distinguished scientists partnering with GIBH
Dr. John Talley is an inventor and researcher with over 25 years experience with
a broad background in organic and medicinal chemistry and an inventor of the COX-2
inhibitor, celecoxib (Celebrex™) and valdecoxib (Bextra™). Dr. Mark Obukowicz was a
Senior Research Fellow at Pfizer Global Research and Development with >26 years
experience in drug discovery and the discoverer of novel chromene, selective inhibitors
of COX-2.
V. Creation of new companies in Guangzhou
In addition to drug development, a key mission of the Pipeline is to create spinoff companies based on intellectual property cultivated in the DDP. This will serve
several purposes. First, it will ensure a focused effort on the development of lead drugs
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into clinical trials; second, it will share the burden of drug discovery, cost and risk across
GIBH and the new companies it creates; and third, stimulate the local economy in
Guangzhou by employing people and investing in the local community. Establishment of
local satellite companies will increase the scientific excellence within the city of
Guangzhou and spur regional growth in the area of biotechnology. Currently the DDP
has mediated the spin-off of two small companies in Guangzhou city including GZstem
and Argo Biopharmaceuticals.
1. GZstem, Inc.
GZstem, is a stem cell based company funded by the US Corporation, Sigma
Aldrich. The product line of the company consists of 1. Induced pluripotent stem cells
(iPSCs), derived from tissue of normal and diseased human specimens (25 lines currently
available); 2. Protocols for directed differentiation of iPSCs, into different cell lineages; 3.
human iPSCs containing reporter genes. GZstem employs 10 full time scientists with a
total operating budget of ¥8.5M/yr.
2. Argo Biopharmaceuticals
Argo Biopharmaceuticals is a technology based company funded by both a
venture capital firm and the local government. The product line of the company is siRNA
based therapeutics using novel nano-particle delivery systems. Argo Biopharmaceuticals
employs 8 full time employees with a total operating budget of ¥6.5M/yr
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