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Drug repositioning: out of the box opportunities despite data and
chemistry challenges
Christopher A. [email protected]
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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.
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Target-based drug discovery:
E1 E5
R2R3
R4R5
R6R1
E2
E3 E4 E7
E6
DP 1 DP 2
D1D2
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….the real picture
R8
DP 5
E10
E9
E8E1 E5
R2R3
R4R5
R6R1
E2
E3 E4 E7
E6
DP 1 DP 2
R7
R9 R10
R11R12
DP 3DP 4
E7
E8
D1D2
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Has drug discovery gone wrong?• Prevailing mantra: identify a mechanism and
discover a selective ligand for a single target
• Counter responses:
• Improve target validation, academic collaboration
• Spread financial risk – collaborations, outsourcing
• Phenotypic screening
• Drug repurposing
• Multi targeted drug discovery
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Phenotypic screening advantageThe majority of small-molecule first-in-class NMEs that were discovered between 1999 and 2008 were first discovered using phenotypic assays (FIG. 2): 28 of the first-in-class NMEs came from phenotypic screening approaches, compared with 17 from target-based approaches.
How were new medicines discovered? David C. Swinney and Jason Anthony Nature Reviews Drug Discovery 2011 (10) 507-519.
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Drugs Under Active Development involved in Multiple Programs
Source: Thomson Reuters Integrity℠
Within Integrity there are over 20,000 active preclinical drug programs.Here we have taken a sample set of 1000 active preclinical drug programs.
Note – this includes all those with anything active in 10 or over programs, hence the apparent increase.
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Phenotypic observations
• 30% of 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
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Unbiased Phenotypic Screening
• “Phenotypic Screening” as often used–Any route to discovery other than “hypothesis-
based” discovery• e.g. Serendipitous finding in the clinic, focused screen in
a single model
• Systematic Unbiased Phenotypic Screen•Melior’s approach involving comprehensive evaluation
in a spectrum of animal models independent of candidates mechanism or primary therapeutic area
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Repurposed diabetes drug
10
Lyn kinase activatornew mechanism,one of 264 mechanism possibilities
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Source: Thomson Reuters Integrity℠
The Key Therapeutic Areas by no. of Associated Targets
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Conclusions
• Drug repurposing is independent of drug discovery method
• Phenotypic screens cast a broad net
• Reductionist / mechanistic approach unnecessarily limits opportunities–eg. current NCATS repositioning
• Chemistry structural information required for most computational approaches–eg. current NCATS missing structures
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