University of Pittsburgh Drug Discovery Institute The Role of - PowerPoint PPT Presentation

University of Pittsburgh Drug Discovery Institute The Role of Systems Biology in Drug Discovery Fifth Annual Ri.MED Scientific Symposium October 24, 2011 D. Lansing Taylor, Ph.D. Director Professor of Computational and Systems Biology 11/4/2011 1 Novel Chemistries and Systems Biology Power Discovery

Agenda 1. Introduction to the Challenge/Opportunity in Academic Drug Discovery 2. Overview of the UPDDI 3. Cellular Systems Biology Program (CSBP) 4. Platform for Protein-Protein Interactions 11/4/2011 2 Novel Chemistries and Systems Biology Power Discovery

Traditional Steps in Drug Discovery and Development at Pharma: Why is it Not Working Well? Chemical libraries/Biologics Pre-discovery Discovery Humans Preclinical studies Target Lead Lab and animal identification identification Clinical trials testing and validation and optimization Up to 15 years and $ 1 billion High attrition rates Very low success rates 3 Novel Chemistries and Systems Biology Power Discovery

What is the State of the Drug Discovery Industry? In the Last 15 Years • Cost of discovering a drug up more than 270% • Number of NME’s approved down more than 50% • Major revenue generators (block busters) going off patent How has the Pharmaceutical Industry Responded? • Merging with other pharma’s to gain short -term pipeline • Decreasing costs by laying off tens of thousands of researchers • Stopping research and development (R&D) in some therapeutic areas • Shifting more R&D to China and India • Exploring Personalized Medicine-drug candidate with diagnostic • Developing more collaborations with academia 11/4/2011 Novel Chemistries and Systems Biology Power Discovery 4

Some Thoughts On How To Be Successful in Academic Drug Discovery 1. Understand what other academic discovery programs are doing 2. Identify and then Integrate strengths across the Institution and key partners 3. Create a “marketing” program to educate industry on capabilities 4. Establish a pharmaceutical industry collaboration program (e.g.Italian Institute of Technology’s D3) 5. Engage industry involved in personalized medicine 6. Select some initial therapeutic focus areas for internal discovery 11/4/2011 5 Novel Chemistries and Systems Biology Power Discovery

Some Existing Pharmaceutical Company Collaborations at the University of Pittsburgh Therapeutic Area Pharmaceutical Company Johnson & Johnson Cancer Janssen Biotech (Centocor) Asthma Janssen Biotech (Centocor) Scleroderma Janssen Biotech (Centocor) COPD Novartis Alpha-1 antitrypsin deficiency Hawthorn Pharmaceuticals Cancer GE Healthcare Alzheimer's Disease Abbott Necrotizing enterocolitis Arno Therapeutics Cancer 11/4/2011 6 Novel Chemistries and Systems Biology Power Discovery

Examples of Successful “Academic” Drugs: This Can Be Done! • Remicade (Infleximab)-tumor necrosis factor α Jan Vilcek and Junming Le New York University-Centocor, Inc. • NYU has received $650M in royalties • Paclitaxel (Taxol)-MT stabilizer (mitotic inhibitor) Robert Holton, Chemist-total synthesis Florida State-Bristol Myers Squibb • Florida State has received $350M in royalties 11/4/2011 Novel Chemistries and Systems Biology Power Discovery 7

Example: Drug Discovered in Italy Biphosphates-Osteoporosis Giorio Staibano and Sergio Rosini Instituto Gentili Research Laboratories in Pisa 11/4/2011 8 Novel Chemistries and Systems Biology Power Discovery

Agenda 1. Introduction to the Challenge/Opportunity in Academic Drug Discovery 2. Overview of the UPDDI 3. Cellular Systems Biology Program (CSBP) 4. Platform for Protein-Protein Interactions 11/4/2011 9 Novel Chemistries and Systems Biology Power Discovery

Drug Discovery in BST-3 at the University of Pittsburgh University of Pittsburgh Biomedical Science Tower 3 4 Novel Chemistries and Systems Biology Power Discovery

Leadership of the UPDDI Associate Director Associate Director Chemistry Comp & Sys Biol Peter Wipf Ivet Bahar Director Associate Director Associate Director Lans Taylor Cancer Institute Med-Chemistry Dept. Medicine Barry Gold Edward, Chu, MD 1 Novel Chemistries and Systems Biology Power Discovery 1

Distributed Structure Of UPDDI Focused Screening Discovery & Support for Focused Development Collaborative Discovery and Projects Development Development Portfolio Chemistry & Biologics Medicinal Technology Drug Discovery Chemistry Developments & & Development Corporate Core Collaborations & In Vitro Licensing Safety & Metabolism Pre-Clinical Educational Studies Formulations Programs & Delivery Animal Efficacy Animal Tox & Pharmacokinetics Novel Chemistries and Systems Biology Power Discovery 12

We have the Capabilities: Prominent Centers, Institutes & Departments Novel Chemistries and Systems Biology Power Discovery

Initial Focus Areas • Selected two therapeutic areas for initial focus where we have great strengths, while supporting any therapeutic area brought to us by faculty or industry • Cancer • Neurological Diseases • Selected three technical areas for initial focus where we have unique strengths, while harnessing all technologies • Novel Chemistries including Biologics • Computational Chemistry (Includes Structural Biology) • Computational Biology and Systems Biology 14 Novel Chemistries and Systems Biology Power Discovery

Novel Chemistries from Pitt: Two Examples from Multiple Faculty in A&S, SOM & SOPharm Peter Wipf, Ph. D. Distinguished University Edward Chu, M.D. Professor of Chemistry Professor of Medicine Chief, Division of Hematology/Oncology Deputy Director of UPCI Chinese Herbal Medicines PHY906 -Combination with cytotoxic chemotherapy in metastatic colorectal cancer Combinatorial Chemical Diversity -Phase 1-2 Chemistry Center Center Phase 2 Clinical trials (Glioblasoma multiforme and Prostate) -PI3 Kinase 11/4/2011 Novel Chemistries and Systems Biology Power Discovery 15

Computational Chemistry/ Biology & Systems Biology Mapping of complete set of FDA approved drugs and their targets Extracted from DrugBank (Sept 2010). Ivet Bahar, Ph. D. Chair, Department of Computational and Systems Biology Predicting protein interaction dynamics using elastic network models 1 (1) Bahar et al (2010) Annual Rev Biophys 39, 23-42.; (2) Liu, Eyal & Bahar (2008) Bioinformatics 24, 1243-50. 11/4/2011 Novel Chemistries and Systems Biology Power Discovery 16

Vision To build an Institute that applies novel and traditional technologies to optimize the discovery and development of new molecular entities (NME’s) through integrated activities across departments, institutes and commercial partners, while advancing the science and technology of drug discovery 1 Novel Chemistries and Systems Biology Power Discovery 7

Agenda 1. Introduction to the Challenge/Opportunity in Academic Drug Discovery 2. Overview of the UPDDI 3. Cellular Systems Biology Program (CSBP) 4. Platform for Protein-Protein Interactions 11/4/2011 18 Novel Chemistries and Systems Biology Power Discovery

Bridge between Molecular and Cellular Dynamics and Physiology: Computational and Systems Biology Addressing the Biological Complexities Center for Biologic Imaging  -------- 25 Å ------  Neil Hukreide, Ph.D. Bert Gough, Ph.D., Lei Yang, Ph.D. Gary Silverman, M.D., Ph.D. Andreas Vogt, Ph.D. Tim Lezon, Ph.D. Stephen Thorne, Ph.D. Cecilia Lo, Ph.D David Perlmutter, M.D. Novel Chemistries and Systems Biology Power Discovery

Heterogeneity of Response to Therapeutics in Cell Populations: Treatment of Tumors Cancer Cell Lines TME Bert Gough, Ph.D. Patient Samples Tim Lezon, Ph.D. Lans Taylor, Ph.D. & Jennifer Grandis, M.D., FACS Tobacco Grant Funding 20 Novel Chemistries and Systems Biology Power Discovery

Heterogeneity of Drug Responses in Tumors and Pathway Modulations Adapted from Huang (2009) Development 136: 3853 Heterogeneity Macroheterogeneity in a cell population Cell count Genetic Non-genetic Microheterogeneity clonal population Extrinsic Intrinsic cell parameter 1 Macroheterogeneity Microheterogeneity Population noise Temporal noise 11/4/2011 21 Novel Chemistries and Systems Biology Power Discovery 21

Platform for Cellular Systems Biology Server Room Protocol Sample InCell 6000 Data Data Data Development Prep Acquisition Process Mining/Visualization VMware ESXi hosts (3) Gig-E Computational & Systems Network Printers, Copiers, Scanners 4Gbps FC optical Biology Promise Vtrak (11TB) PITTnet Each Cluster has login node DMZ and dedicated Gig-E VLAN private network Internet Cluster 1 864 CPU cores 1388 GB ram 75 nodes on Infiniband 6 -384 Well Workstation Misc Servers Gig-E VLAN Cluster 2 Plates 802.11g Wireless Access Points (4) 46 CPU cores 124 GB ram Wireless Cluster 3 124 CPU cores Cell Data Sample Store 132 GB ram Database Database Database Cluster 4 40 CPU cores Desktops / Classroom Miscellaneous 40 GB ram Workstations (90+) Laptops (23) Laptops (20+) Novel Chemistries and Systems Biology Power Discovery 22

High Content Analysis Single Well 4x 10,000 cells Higher Magnification Multiple Biomarkers 384 Well Plates 23 Novel Chemistries and Systems Biology Power Discovery