SLAS2013 Drug Repurposing SIG Meeting

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Can target-based drug discovery be reconciled with phenotypic assays in the context of drug repurposing? One of the questions discussed at the SLAS Drug Repurposing SIG meeting at SLAS2013.

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SLAS2013 Drug Repurposing SIG Meeting

  1. 1. Best Strategies to Undertake a Drug Repurposing Initiative1 © 2009 PerkinElmer
  2. 2. Objectives Can target-based drug discovery be reconciled with phenotypic assays in the context of drug repurposing? What are the best practices in assay design? How should compounds be tackled?2
  3. 3. Attrition rates by phase The Productivity Crisis in Pharmaceutical R&D, Fabio Pammolli, Laura Magazzini and Massimo Riccaboni, Nature Reviews Drug Discovery 2011 (10) 428-438.3
  4. 4. Phenotypic vs Target Based R&D How were new medicines discovered? David C. Swinneyand Jason Anthony Nature Reviews - Drug Discovery, vol.10 p507 20114
  5. 5. Phenotypic vs Target Based R&D How were new medicines discovered? David C. Swinneyand Jason Anthony Nature Reviews - Drug Discovery, vol.10 p507 20115
  6. 6. Phenotypic vs Target Based R&D 19/20th century 20/21st century (serendipity, RDD) (technology, industrialization) then! now what?6
  7. 7. Drug Discovery Processes Traditional:“target-driven” Target ID & Val Reverse Pharmacology: “Phenotypic” Lead Drug Discovery Lead In cellulo/vitro Optimization In vivo testing testing Candidate Mechanistic Development Study Drug7
  8. 8. Phenotypic vs Target Based R&D Target Based Phenotypic • Compatible with both small • Compatible with both small molecules molecules and biologics and biologics • Controlled environment • Complex environment  Simplistic / “one-dimensional”  “Black-box”/ multifactorial  avoid off-target artifacts  In-vivo / In vitro platforms  robustness and reproducibility  Multiple targets & interactions • Molecular mechanism of action • Molecular mechanism of action  Pharmacodynamics studies  Pharmacokinetics / ADMET (Kd, Ki, etc) functional studies • Well suited for: • Well suited for:  Intractable targets (eg. lipid  Drug repositioning / repurposing kinases)  Fragment-based screening8
  9. 9. “Target-based Shotgun” characterization: in vitro/cellulo molecular signature9
  10. 10. In cellulo / vivo molecule signatures10
  11. 11. Reconciling phenotypic and target-driven observations 30% o f 400 compounds profiled show new beneficial biology Up to 90% of new indications are driven by “on-target” activities Biology is complex and there is a tremendous amount that is not understood Phenotypic screening provides an opportunity to identify new clinically relevant uses of existing molecules driven by action on known molecular targets Lipinski - Arrowhead SFO 2012 side vs off target effects?11
  12. 12. Success stories: Melior Pharmaceuticals (CRO)12
  13. 13. Success stories: Lilly / USC Partnership13

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