Drug Discovery Pipeline Overview 2011 -...

Guangzhou Institutes of Biomedicine and Health

Drug Discovery PipelineOverview 2011

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Goal of the Pipeline

Stem Cell Biology & Regenerative

Medicine (iSCBRM)

Chemical Biology (iCB)

Infection & Immunity

(I3)

Drug Discovery Pipeline(DDP)

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

GIB

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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.

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Milestones for the Pipeline

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)

Milestone 1: Centralizing Key Technology Groups

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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 & CrystallographyAllows us to optimize lead compounds using computer aided design as well as virtual screening

Pharmacokinetics/ADMEDefines the PK and safety properties of our lead compounds

BiomarkersValidates the efficacy and safety of our drugs in pre-clinical models

Medicinal ChemistryDesign, synthesis and formulation of new drugs with IP

Bio-TherapeuticsThe use of proteins as active agents to treat diseases

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Pipeline Organization in 2011Micky Tortorella (CTO)

Administration: 3 FTE

Chemistry (Ding Ke): 18 RA

Biology (Donghai Wu): 11 RA

HTS (Zhengchao Tu): 5 RA

PK/ADME (Xiaorong Liu): 9 RA

Crystallography (J. Liu): 1 RA

Biomarkers (S. Spillman): 2 RA

Bio-Therapeutics (D. Yu): 2 RA

• Total Headcount is 53 full time employees

• Budget per year is > ¥23 M

• Targeted Headcount is 65 full time employees


Impact of HTS (Milestone 1) • High Throughput Screening (HTS) group currently runs kinase, protease, and various cell-based assays to support several drug discovery projects at GIBH.

Productivity 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.

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Targets (Related diseases ) Hits identifiedProtein KinasesABL (CML) and mutants 351 ALK (Cancer) 5Kit (GIST) (Cancer) 231 EGFR (Breast and lung cancer) and mutants 347 Her2 (Breast cancer) 84 AKT1 (Cancer) 35 AKT2 (Cancer) 35 AKT3 (Cancer) 35 ProteasesDPPIV (Diabetes) 50DPP8 (Diabetes) 17DPP9 (Diabetes) 38Other molecular targetsNeuraminidase S (Influenza) 32 Neuraminidase S (Influenza) 32HDAC1（Cancer） 15HDAC7 （Cancer） 15Cell-based infectious diseasesInfluenza 62 Ev71(Enterovirus infection) 1


Impact of PK/ADME (Milestone 1)

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• Pharmacokinetics (PK) group has been formed and centralized to support the drug discovery research at GIBH

• 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

Productivity Team MembersAnalysis Compounds

Tested Pharmacokinetics 85 CNS penetration 7 Acute toxicity 10Metabolic stability 35 Protein binding 28 Caco2 21 Drug drug interaction 81Zebra Fish (Toxicity) 16Rat air pouch inflammation model

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Drug toxicity in rat 4 Human hepatocyte culture 2


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• 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 Disease

ADAMTS4/5 Arthritis

p38 alpha, beta, delta, gamma Cancer etc.

cKIT/AKT1/EGFR Cancer etc.

Plasmepsin II/IV/V Malaria

G1B Diabetes etc.

Impact of Crystallography (Milestone 1)

• Examples of structural analysis enabling optimization of lead molecules for several projects


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.


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Cell free expression of target protein

Oxidative modification

1. Developing micro-array chips

2. Making Ab chips for rapid biomarker screening

Microarray Slides

3. Validating Nucleic Acid Programmable Protein Arrays


Impact of Medicinal Chemistry (Milestone1)

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• Medicinal chemistry is designing and synthesizing novel drugs against multipletargets in several disease areas including cancer, arthritis, diabetes, CNS and infection. The new chemistries developed at GIBH enjoy strong intellectual property.

Productivity Team MembersTarget Disease # of Compounds

Cancer 300 Arthritis 100 Alzheimer’s 200 Diabetes 100 Flu 120 Malaria 6 Pain 3

Successful assimilation of several project teams:

Measurable impact!


Milestone 2: Formation of Project Teams

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Project

Chemistry Leader

Team Members

Molecule designSynthesis

PurityCrystallography

Scale-upFormulations

Team MembersProtein

ScreeningEnzymologyBiomarker validation

Animal modelsPK/ADME

Safety

Biology Leader

• 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

1. Oral Kinase Inhibitor

2. Oral Anti-AD Compound

3. Anti-Inflammatory siRNAs

4. Plasmepsin V Inhibitor

5. Chromene COX-2 Inhibitor

Sustainable Pipeline of Projects (Milestone 2)

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• Current programs are developing drugs to treat Alzheimer's, leukemia, inflammationand infectious diseases

• 2 projects near Candidate Selection, 1 project at Lead Optimization, 3 projects at Hit Identification and several projects at Early Exploration

Early Exploration

Hit Identification

Lead Optimization

Drug Candidate Selection

Clinical Testing

ADAMTS InhibitorAnti-Inflammatory siRNAs3rd Gen. COX-2 InhibitorPlasmepsin V Inhibitor

ADAMTS-13Cartilage Re-growth

Discovery Pre-Clinical Development Clinical

Development

2nd Gen. Kinase InhibitorOral Anti-AD drug


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Disease: Leukemia(Ding Ke)

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: 2011 2011/2012

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• Pipeline will focus the majority of resources on these two projects in 2011• Resource to win!

Advanced Projects (Milestone 2)

IC50 nMcompd Bcr-Abl Bcr-Abl(T315I) K562 Ba/F3 (T315I)

Imatinib 399 >10000 280 35000

Nilotinib 14 >10000 22 28000

Dasatinib 3.0 >10000 13 19000

D824 1.0 12 0.24 46

Candidate compound D824 inhibits the resistant forms

Guangzhou Institutes of Biomedicine and Health3rd Gen. Kinase Inhibitor for the treatment

of Leukemia (Milestone 2)

Efficacy of D824 in a model of cancer

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Guangzhou Institutes of Biomedicine and HealthOral Anti-Alzheimer’s Disease Drug

(Milestone 2) 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

Activity in vivo 100 times more potent than Minozac

PK

F%, T1/2 74.91%， 4.32 ± 2.62 h

BBB penetration3 times better than MinozacAUC(Brain/Plasma)=0.21

Metabolism Stable in rat, human

Safety Acute toxicity MTD > 2000mg/kg

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0.01pM0.1pM

10pM1pM

100pM 1nM

10nM100nM

1uM10uM

100uM1mM

Treatment Concentration

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第一天第二天第三天第四天第五天

游泳

时间

(s)

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)

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In vitro activity In vivo activity Acute toxicity15

Delivery DevicesPositively charged nanoplexes

Pre-filled syringes

Target SitesChondrocytesSynoviocytesBone cellsImmune cells (RA)

DrugssiRNA-AS001

siRNA targeting inflammatorygenes involved in OA and RA

Sustain Drug Release viaspecialized Delivery System

(2) Intra-articular Strategy for Commercializing siRNA in OA and RA

Anti-Arthritis siRNA Drugs for Local delivery into Joints (Milestone 2)

(1) Slow Release siRNA Drug Delivery System

IC50~10pM

nanoplexes

Biodegradablepolymer

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Milestone 3: International Partnerships

Plasmepsin V Inhibitors for

Malaria

The Center for World Health & Medicine, Saint Louis University

GIBH

Washington University

3rd Gen. COX-2 Inhibitors for

Pain & Cancer

Legacy Pfizer Scientists,

Inventors of Celebrex

GIBH


Milestone 4: Creating New Companies

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Stem Cell Biology & Regenerative

Medicine (iSCBRM)

Chemical Biology (iCB)

Infection & Immunity

(I3)

Drug Discovery Pipeline

(DDP)

Argo Biopharmaceuticals

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• 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

Transfer of Intellectual Property

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Mission of New Companies (Milestone 4)

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 genesPartner: Sigma, USAOperating Budget: ¥10 M/yrPeople: 10 full time employeesLocation: Guangzhou

Product Line: 1. siRNA based therapeutics. 2. Nano particle delivery systems.Partner: Venture Capital and Local GovernmentOperating Budget: ¥6-7 M/yrPeople: 8 full time employeesLocation: Guangzhou

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Introduction of Micky TortorellaExperience in Drug Discovery1. (1992-1999): DuPont Chemical as a Research Scientist studying

inflammatory diseases, matrix and proteinase biology.

2. (2001-2003): Pharmacia as a Senior Principal Investigator and project leader in musculoskeletal diseases.

3. (2003-2009): Pfizer as a Senior Principal Investigator and project leader in inflammatory diseases.

4. (2009-now): GIBH as Chief Technology Officer in drug discovery research

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 2009.

Recipient of awards, including the PGRD Individual Achievement Award at Pfizer.

Primary author on > 47 publications and inventor of 10 US patents.

Scientific Accomplishments

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Drug Discovery Pipeline Overview 2011 -...

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