Drug Discovery Pipeline Overview 2011

Transcription

1 Guangzhou Institutes of Drug Discovery Pipeline Overview

2 Goal of the Pipeline Guangzhou Institutes of Mission: Capture the best ideas from the 3 scientific institutes at GIBH and translate the ideas into drug discovery projects. In the past there was no mechanism to transform a concept into a drug discovery project Lack of incentive, platform technologies, centralization and integration of disciplines GIBH Scientific Institute Stem Cell Biology & Regenerative Medicine (iscbrm) Chemical Biology (icb) Infection & Immunity (I3) Drug Discovery Pipeline (DDP) Drug Candidates & Clinical Trials DDP Goal: Provide the expertise, platform, key technologies, integrated project teams and funding to develop new drugs for the treatment of cancer, inflammation and infection. 2

3 Milestones for the Pipeline Guangzhou Institutes of 1. Create and centralize key technology groups to support projects 2. Form integrated teams to develop a sustainable pipeline of projects 3. Establish key international partnership to co-develop drugs 4. Create new companies in Guangzhou using IP matured in the Pipeline Drug Discovery Pipeline (DDP) 3

4 Milestone 1: Centralizing Key Technology Groups High Through-Put Screening (HTS) Capable of screening thousands of compounds per week in various enzyme and cell based assays at a low price Structural Biology & Crystallography Allows us to optimize lead compounds using computer aided design as well as virtual screening Pharmacokinetics/ADME Defines the PK and safety properties of our lead compounds Biomarkers Validates the efficacy and safety of our drugs in pre-clinical models Medicinal Chemistry Design, synthesis and formulation of new drugs with IP Bio-Therapeutics The use of proteins as active agents to treat diseases 4

5 Pipeline Organization in 2011 Guangzhou Institutes of Micky Tortorella (CTO) Administration: 3 FTE Chemistry (Ding Ke): Biology (Donghai Wu): 18 RA 11 RA Total Headcount is 53 full time employees Budget per year is > 23 M Targeted Headcount is 65 full time employees HTS (Zhengchao Tu): PK/ADME (Xiaorong Liu): Crystallography (J. Liu): 5 RA 9 RA 1 RA Biomarkers (S. Spillman): 2 RA Bio-Therapeutics (D. Yu): 2 RA 5

6 Impact of HTS (Milestone 1) Guangzhou Institutes of High Throughput Screening (HTS) group currently runs kinase, protease, and various cell-based assays to support several drug discovery projects at GIBH. Productivity Targets (Related diseases ) Hits identified Protein Kinases ABL (CML) and mutants 351 ALK (Cancer) 5 Kit (GIST) (Cancer) 231 EGFR (Breast and lung cancer) and mutants 347 Her2 (Breast cancer) 84 AKT1 (Cancer) 35 AKT2 (Cancer) 35 AKT3 (Cancer) 35 Proteases DPPIV (Diabetes) 50 DPP8 (Diabetes) 17 DPP9 (Diabetes) 38 Other molecular targets Neuraminidase S (Influenza) 32 Neuraminidase S (Influenza) 32 HDAC1(Cancer) 15 HDAC7 (Cancer) 15 Cell-based infectious diseases Influenza 62 Ev71(Enterovirus infection) 1 Team Members Cloning and expression >20 targets have been cloned and 7 of them have been transfected into insect cells and their purification are underway. 6

7 Impact of PK/ADME (Milestone 1) Pharmacokinetics (PK) group has been formed and centralized to support the drug discovery research at GIBH Guangzhou Institutes of The group is supporting several projects, including our lead oral kinase inhibitor project for the treatment of leukemia and an oral anti-inflammation compound program for the care of Alzheimer's disease Analysis Productivity 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 2 inflammation model Drug toxicity in rat 4 Human hepatocyte culture 2 Team Members 7

8 Guangzhou Institutes of Impact of Crystallography (Milestone 1) The Protein/Crystallography group is supporting projects in the DDP by (1) Expression of protein and crystallography, (2) Computer-aided drug design, (3) High-throughput virtual screening, and (4) Development of a super computer platform capable of virtually screening ~40M compounds Target ADAMTS4/5 Productivity Disease Arthritis Team Members p38 alpha, beta, delta, gamma ckit/akt1/egf R Plasmepsin II/IV/V G1B Cancer etc. Cancer etc. Malaria Diabetes etc. Examples of structural analysis enabling optimization of lead molecules for several projects 8

9 Guangzhou Institutes of Impact of Biomarkers (Milestone 1) 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 drug candidates by monitoring the modulation of these biomarkers. Productivity Team Members 1. Developing micro-array chips Microarray Slides 2. Making Ab chips for rapid biomarker screening Oxidative modification 3. Validating Nucleic Acid Programmable Protein Arrays Cell free expression of target protein 9

10 Guangzhou Institutes of Impact of Medicinal Chemistry (Milestone1) Medicinal chemistry is designing and synthesizing novel drugs against multiple targets in several disease areas including cancer, arthritis, diabetes, CNS and infection. The new chemistries developed at GIBH enjoy strong intellectual property. Target Disease Productivity # of Compounds Team Members Cancer 300 Arthritis 100 Alzheimer s 200 Diabetes 100 Flu 120 Malaria 6 Pain 3 10

11 Guangzhou Institutes of Milestone 2: Formation of Project Teams Integration of medicinal chemistry and biology has been successful Project teams provide the critical mass and expertise needed to support and advance drugs in the pipeline Project Successful assimilation of several project teams: Biology Leader Team Members Protein Screening Enzymology Biomarker validation Animal models PK/ADME Safety Team Members Molecule design Synthesis Purity Crystallography Scale-up Formulations Chemistry Leader 1. Oral Kinase Inhibitor 2. Oral Anti-AD Compound 3. Anti-Inflammatory sirnas 4. Plasmepsin V Inhibitor 5. Chromene COX-2 Inhibitor Measurable impact! 11

12 Sustainable Pipeline of Projects (Milestone 2) Discovery Pre-Clinical Development Clinical Development Early Exploration ADAMTS-13 Cartilage Re-growth Hit Identification Lead Optimization Anti- ADAMTS Inhibitor Inflammatory sirnas 3 rd Gen. COX-2 Inhibitor Plasmepsin V Inhibitor Drug Candidate Selection 2 nd Gen. Kinase Inhibitor Oral Anti-AD drug Clinical Testing Current programs are developing drugs to treat Alzheimer's, leukemia, inflammation and infectious diseases 2 projects near Candidate Selection, 1 project at Lead Optimization, 3 projects at Hit Identification and several projects at Early Exploration 12

13 Advanced Projects (Milestone 2) Guangzhou Institutes of Disease: Leukemia (Ding Ke) 1 2 Alzheimer's (Wenhui Hu & Donghai Wu) Target: Kinases Neural Inflammation Drug: Oral small molecule Oral small molecule Mechanism of Action: Inhibition of several kinases linked to cancer metastasis Suppression of inflammation associated with amyloidal plaques Stage of Development: Candidate Selection Candidate Selection Time to IND filing: /2012 Pipeline will focus the majority of resources on these two projects in 2011 Resource to win! 13

14 3 rd Gen. Kinase Inhibitor for the treatment of Leukemia (Milestone 2) Guangzhou Institutes of Efficacy of D824 in a model of cancer Candidate compound D824 inhibits the resistant forms IC50 nm compd Bcr-Abl Bcr-Abl(T315I) K562 Ba/F3 (T315I) Imatinib 399 > Nilotinib 14 > Dasatinib 3.0 > D

15 Oral Anti-Alzheimer s Disease Drug (Milestone 2) Guangzhou Institutes of Candidate HWH-2-130: Biological profile of an oral anti-ad drug Compound 130 has excellent drug-like properties. The animal studies show that 130 blocks neuron-inflammation and is efficacious in models of Alzheimer s disease and stroke. Physical properties Rule of five No violations PD Activity in vitro 1.74nM, > Minozac 4000-fold PK Activity in vivo F%, T1/2 BBB penetration Metabolism 100 times more potent than Minozac 74.91%, 4.32 ± 2.62 h 3 times better than Minozac AUC(Brain/Plasma)=0.21 Stable in rat, human Safety Acute toxicity MTD > 2000mg/kg 60 % of Maximum Activity pM 0.1pM 100pM 10pM 1pM 100nM 10nM 1nM ZGF uM 10uM 1uM Treatment Concentration 1mM 游泳时间 (s) ## ** * * ### *** * *** 第一天第二天第三天第四天第五天 sham model 多奈哌齐 Minozac(2.5mg/kg) ZGF-2-130(0.25mg/kg) ZGF-2-130(0.025mg/kg) ZGF-2-130(0.0025mg/kg) *** In vitro activity In vivo activity Acute toxicity 15 ### ** ** **

16 Anti-Arthritis sirna Drugs for Local delivery into Joints (Milestone 2) (1) Slow Release sirna Drug Delivery System Biodegradable polymer (2) Intra-articular Strategy for Commercializing sirna in OA and RA nanoplexes sirna targeting inflammatory genes involved in OA and RA Drugs sirna-as001 Sustain Drug Release via specialized Delivery System Delivery Devices Positively charged nanoplexes Target Sites Chondrocytes Synoviocytes Bone cells Immune cells (RA) IC50~10pM Pre-filled syringes 16

17 Guangzhou Institutes of Milestone 3: International Partnerships Plasmepsin V Inhibitors for Malaria 3 rd Gen. COX-2 Inhibitors for Pain & Cancer The Center for World Health & Medicine, Saint Louis University Legacy Pfizer Scientists, Inventors of Celebrex GIBH GIBH Washington University 17

18 Milestone 4: Creating New Companies Guangzhou Institutes of Stem Cell Biology & Regenerative Medicine (iscbrm) Transfer of Intellectual Property 1 Chemical Biology (icb) Drug Discovery Pipeline (DDP) 2 Infection & Immunity (I3) Argo Biopharmaceuticals Ensures focused effort on the development of lead drugs into clinical trials Shares the burden of discovery across GIBH with the new companies Stimulates the local economy of Guangdong Province Stimulates both science and biotech in Southern China Measurable Impact: 2 companies created 18

19 Guangzhou Institutes of Mission of New Companies (Milestone 4) 1 2 Argo Biopharmaceuticals Product Line: 1. ipscs, derived from tissue of normal and diseased human specimens. 2. Protocols for directed differentiation of ipscs into different cell lineages. 3. human ipscs containing reporter genes Partner: Sigma, USA Operating Budget: 10 M/yr People: 10 full time employees Location: Guangzhou Product Line: 1. sirna based therapeutics. 2. Nano particle delivery systems. Partner: Venture Capital and Local Government Operating Budget: 6-7 M/yr People: 8 full time employees Location: Guangzhou 19

20 Introduction of Micky Tortorella Guangzhou Institutes of Experience in Drug Discovery 1. ( ): DuPont Chemical as a Research Scientist studying inflammatory diseases, matrix and proteinase biology. 2. ( ): Pharmacia as a Senior Principal Investigator and project leader in musculoskeletal diseases. 3. ( ): Pfizer as a Senior Principal Investigator and project leader in inflammatory diseases. 4. (2009-now): GIBH as Chief Technology Officer in drug discovery research Scientific Accomplishments Discoverer of Aggrecanase-1 and -2, enzymes responsible for the breakdown of cartilage in osteoarthritis, published in Science in1999. Co-inventor of novel and proprietary series of amino-2-indanol-based compounds as selective aggrecanase inhibitors published in JBC in Recipient of awards, including the PGRD Individual Achievement Award at Pfizer. Primary author on > 47 publications and inventor of 10 US patents. 20