Why Repurposing Works and How to Pick a Winning Drug
Why Repurposing Works and How to Pick a Winning Drug While Avoiding Failures Christopher A. Lipinski Scientific Advisor MELIOR DISCOVERY http://www.meliordiscovery.com/ Outline Why Repurposing Works – Chemistry Space Phenotypic Versus Mechanistic Two Questions the VC Always Asks Chemistry Information Content Simple Computational Rankings Medicinal Chemistry Pattern Recognition Quality Through an Abundance of Caution CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Why Repurposing Works PC view. HTS on 100,000’s of diverse compounds to get a lead. Why should repurposing ever work? 22,000 genes, > 106 proteins How many MWT 500 compounds in a human? 200 moles x 6.02 *1023 = 1026 Diverse compounds = 1060 Compounds / targets = 10-34 (1 hit / target) Compounds / targets = 10-25 (1 billion hits/ target) Truly diverse library should never give a hit. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 True Diversity Does Not Exist HTS does indeed find hits. True diversity does exist in silico. True diversity does not exist experimentally. chemistry success bias reagent access bias people selection bias CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Biologically Active Space CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Chemistry Space is not Diverse Nature: December 16, 2004 CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Phenotypic Versus Mechanistic Phenotypic screening serendipity - no mechanistic bias experimentally driven approach large target opportunity space exclusive drug discovery approach pre 1980 Chemoinformatic / bioinformatic driven compound - target – disease information computationally driven approach database mining based on what is known narrow target opportunity space CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Two Questions the VC Always Ask #1: Failures in Phase 2 and Phase 3? Lots of opportunity to look at late phase efficacy failures Why Drugs Fail – A Study on Side Effects in New Chemical Entities, Schuster et al., Current Pharmaceutical Design, 2005, 11, 3545-3559 CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Two Questions the VC Always Ask #2: On target or off target? On target new indication is original mechanism 70 – 95% based on 70 literature examples may not need chemistry optimization Off target new use is by a new mechanism may need chemistry optimization CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Chemistry Information Content Structure in CAS SciFinder Cannot run any calculations on a picture. Must capture the compound structure in machine (computer) readable format. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Translate into *.mol Format CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 The Vioxx Connection Table CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Structure Capture Reference http://www.accelrys.com/reference/publications/pub_lipinski.php CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 SciFinder Search on Vioxx CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 1480 Results by Document Type CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 593 Patent Documents on Vioxx CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Vioxx Patent Year Analysis CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Sources of Clinical Data IDDB (Thomson Scientific) Pharmaprojects (PJB Publications) Integrity (Prous Science) Compendium of New Drug Approvals in eleven industrialized countries 1970-1983 (FDA) UN withdrawn drugs list (ISBN 92-1-130230-7) CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Indications Discovery Substrate Pool and Stream IDdb references 20,000 “compounds”. 5,000 listed “discontinued”. 1,500 discontinued for non-safety reasons. 500 pass Melior first-tier criteria. Eliminate cmpnds to very well vetted targets. COM patent expired. Eliminate anti-infectives, anti-cancer. Misc. 120 Lipinski “approvable”. 150 orally active compounds discontinued / year. > 10 / year are Lipinski “approvable”. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Simple Computational Rankings Drug-like properties Required for an orally active drug: soluble permeable metabolically stable reaches target sufficient concentration sufficient duration sufficient therapeutic ratio CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 A Proliferation of Useful Rules Rule of 5 for oral activity. Rule of 3 for fragment screening. Less than 10 rotatable bonds for bioavailability. PSA < 60-70 A^2 for CNS activity. N+O <= to 5 for CNS activity. Log P - (N+O) is positive for CNS activity. Log D > 0 and < 3 for good permeability. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Rishton Filters Drug Discovery Today, 2003, vol 8, no 2, 86-95. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Covalent Chemistry CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 GSK Filters for Reactive Groups Strategic Pooling of Compounds for High-Throughput Screening, Hann, M., Hudson, B., Lewell X., Lifely, R., Miller, L., Ramsden, N., J. Chem. Inf. Comput. Sci.; 1999; 39(5) 897 – 902 http://pubs3.acs.org/acs/journals/supporting_information.page?in_manuscript=ci990423o CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Compound Quality Filters Value Judgements Compounds may be excluded from screening based on value judgements: exclude beta lactams exclude steroids exclude flavones exclude phospholipids exclude carbohydrates exclude natural products CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 HERG Activity in Older Drugs 30% of CNS compounds potentially have HERG issues. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 Medicinal Chemistry Patterns “Reality” depiction in chemistry is incomprehensible to biology / genomics. Chemistry is much closer to pathology than to biology / genomics. Graphical pattern recognition is the forte of chemists. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 The Amygdala and Memory Chemists are particularly social. Chemists are superb at pattern recognition. Structural context of “negative” compounds is locked into the amygdala. Rapid effortless chemistry memory retrieval. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006 An Abundance of Caution Rules play to the probability. Filter ruthlessly unless you are really sure. Every compound should be pristine. CBI, Drug Repurposing, Philadelphia, 2006 Copyright Melior Discovery Inc. 2006
© Copyright 2024