The phenotypic screens described in the accompanying Discovery Pipeline proposal do not directly identifythe small-molecule target, yet target identification is vitally important to follow-up, medicinal chemistry efforts.Target identification, including both the therapeutic target and 'off targets' that can result in unwanted 'sideeffects', enables optimization of a compound's selectivity and reduction in the potential for side effects of aresultant drug. Target discovery and validation as it is currently practiced is a significant bottleneck to drugdiscovery. This proposal offers a solution to the target identification problem through the systematic use ofthree distinct and interdisciplinary approaches. Proteomic, genetic and computational methodologies havebeen developed at the Broad Institute and will be implemented as a critical follow-up to screening results.Specifically, we will: 1) develop a systematic, proteomic approach to identify targets that underlie smallmoleculescreening discoveries; 2) combine small-molecule and RNAi methods to identify or to validatetargets that underlie small-molecule screening discoveries; and 3) develop computational methods based ongene expression, small-molecule screening, and proteomic and RNAi data to identify pathways and targetsthat underlie small-molecule screening discoveries. The problem of target identification is one that may besolved not by a single 'killer' technology; rather, we envision the analytical integration of multiple,complementary approaches. Each of these is dependent upon a focused, interdisciplinary effort to a problemthat is unlikely to be solvable with the expertise of one discipline alone.We are proposing to develop small-molecule drugs to alleviate unmet medical needs. In order to maximize adrug's potency and minimize a drug's unwanted side-effects, we need to understand all the proteins('targets') that a drug candidate will interact with. This proposal seeks to use a combination of cutting-edgescientific approaches available at the Broad Institute to address the difficult problem of target identification.
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