Academic Drug Discovery in the Center for Integrative Chemical Biology and Drug Discovery

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1 Academic Drug Discovery in the Center for Integrative Chemical Biology and Drug Discovery Stephen V. Frye, Ph.D. University of North Carolina Chapel Hill

2 Outline Why Academic Drug Discovery? Center for Integrative Chemical Biology and Drug Discovery Vision Mission Capabilities Process & Portfolio Highlights

3 Source of Innovative New Drugs 252 NDA ( ) 18% 24% 58% Pharma Biotech Academic 118 novel 31% 44% 25% 11% 134 me-too 18% 71% Kneller, R. The importance of new companies for drug discovery: origins of a decade of new drugs. Nat Rev Drug Discov 9, (2010). Stevens, A.J. et al. The Role of Public-Sector Research in the Discovery of Drugs and Vaccines. New England Journal of Medicine 364, (2011). Slide courtesy of Tim Willson, GSK

4 The Challenge of Pioneer Drug Discovery Yearly FDA Approvals Public Data from Center of Drug Evaluation and Research: New Drug Approvals New Chemical Entities Priority Reviewed NCEs Investment in pharmaceutical R&D has risen dramatically from ( st decrease!) Number of pioneer drugs (Priority Reviewed NCEs) has not increased >90% failure rate in clinical trials for pioneer drugs due to lack of efficacy Slide courtesy of Tim Willson, GSK

5 Survey of Academic Drug Discovery Centers Collaboration with Rudy Juliano (UNC-SOP) to determine current status of academic and nonprofit drug discovery in US Ca. 80 centers identified, >70% responded to a webbased survey that explored: Mission, organizational model, staffing, funding Therapeutic and technology focus Innovative posture Portfolio results to date Contrasts to for-profit activities Expectations for the future

6 Survey Results: Innovative Posture Target Portfolios by Degree of Validation 7.27% 17.57% 48.61% 26.55% Innovative Clinical Val Preclinical Val Undisclosed

7 Survey Results: Expertise Comparison Comparison Between Industry and Academia Medicinal Chemistry 3.64% 16.36% 23.64% 3.64% 52.73% Organizational Commitment & Stability Assay Development and Screening 18.18% 7.273% 34.55% 40% Aligned with Needs and Values of Society US Academic Drug Discovery Stephen V. Frye*, Marina D. Crosby, Teresa P. Edwards & Rudolph L. Juliano* Nature Reviews Drug Discovery, June 2011, % 10.91% 25.45% % 3.64% 23.64% 30.91% 20% 20% 40% Innovation 30.91% 1.82% 5.45% 40% 21.82% Disease Expertise 38.18% 3.64% 16.36% 41.82% much better in industry somewhat better in industry about the same somewhat better in academia much better in academia

8 Founding the Center Why Academic Drug Discovery For Me? 20 years at Glaxo, GlaxoWellcome, GSK Co-inventor & Research Project Leader for Avodart Dual 5α-reductase inhibitor for treatment of prostatic diseases >$ 1 billion in sales in 2010 Established Glaxo Kinase Chemistry Department in FDA approved kinase inhibitors discovered in this department Last role = World-wide VP, Discovery Medicinal Chemistry Left in 2007 Medicinal chemistry has much to offer in academics

9 Center for Integrative Chemical Biology and Drug Discovery Vision: The Center will be an innovative and sustainable scientific force in the creation of new small molecule therapeutics to improve public health, to transform the drug discovery paradigm and to place UNC at the forefront of translational medicine.

10 CENTER Mission Target Proposals from UNC Faculty responsive collaborations ONCOLOGY FOCUS Center Initiated Projects in Chemical Biology prospective science EPIGENETICS FOCUS small molecule probes target validation drug leads

11 CENTER Capabilities Assay Development (Bill Janzen) 7 scientists protein expression & purification cell-based or in vitro assays multiple platforms & readouts possible Compound Screening screens up to 100K compounds possible >5 HTS run since 4Q09 Small tube store for compound management Medicinal Chemistry (Jian Jin & Xiaodong Wang) 10 internal chemists can support 3-5 projects 4 external chemistry FTEs to support projects and tool compound synthesis Computational Chemistry (Dmitri Kireev + postdoc) design of focused screening sets, virtual screening structure-based design IT infrastructure

12 Envisioned process at UNC for responsive projects Target I.D. & Validation Investigator driven target proposals with validation data from HT-genomics, HT sirna, In vivo models 1 year, 50% success Hit I.D. Assay development MTS, focused sets, knowledge -based design, HTS 1 year, 80% Lead I.D. SAR dev., compd optimiz., Cellular - in vivo efficacy, initial dmpk, selectivity profiling, target validation 2-3 yrs, 50% Candidat e I.D. lead opt., In vivo efficacy & safety, 7 day tox., scale-up, dmpk in 3 species, target validation

13 UNC Collaborations Drop by & chat Reviewed by Center Faculty General Criteria: Disease relevance of target/pathway Potential scientific impact of small molecule tools Tractability of assay development and ligand discovery Portfolio balance and fit with center expertise Funding status & prospects 13

14 Portfolio Model Number of items Preproject projects Assay Develop ment 10 projects Chemistry(H2L) 5 projects Work in progress Effort 14 Project Progress

15 Portfolio Goals 2011 Stage Assay Developed Validated Hits Leads/probes Goals projects that will complete the indicated stage during this year Oncology Epigenetics PAP A1 1Q Mer cellular 2Q CCR7 2Q RGS 2Q LKB1 1Q IKK panel (4) - 1Q 53BP1-2Q IDH1-1Q TRAI 1Q GAPDHS 1Q SETD7 3Q LKB1 2Q Mer backup series 3Q CCR7 3Q/4Q ROR2 2Q RGS 3Q/4Q L3MBTL 1 Irrev. 1Q IKKε/TBK1 2Q TRA1 2Q GAPDHS 1Q 53BP1 2Q SETD7 4Q L3MBTL 1 2Q L3MBTL 3 2Q DNMT3b or SETD8 4Q FS D2 4Q MER Candidate ( )

16 Center Funding Sources (Total = $2.8M) UCRF NCI contracts Grants Philanthropy Do not value money for any more nor any less than its worth; it is a good servant but a bad master. Alexandre Dumas UCRF = University Cancer Research Fund (State)

17 CENTER Mission Target Proposals from UNC Faculty responsive collaborations ONCOLOGY FOCUS Center Initiated Projects in Chemical Biology prospective science EPIGENETICS FOCUS small molecule probes target validation drug leads

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19 How can academic drug discovery succeed where pharma is failing? The goals are not the same Creating new knowledge Focus on innovation and impact Competitive for funding Training young scientists Improving healthcare

20 Acknowledgements UNC & CICBDD Holden Thorpe Bob Blouin Shelley Earp Gary Johnson Alex Tropsha Structural Genomics Consortium, Toronto Aled Edward Cheryl Arrowsmith Peter Brown Bryan Roth Mark Zylka Bill Janzen Jian Jin Dmitri Kireev Xiaodong Wang Barbara Dearry Funding NIH: American Recovery and Reinvestment Act - RC1GM Carolina Partnership/Lineberger Cancer Center/University Cancer Research Fund/ NCI NeXT and CBC Network