Application of Chemoproteomics to Drug Discovery: Identification of a Clinical Candidate Targeting Hsp90

SummaryA chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a data-driven selection of both the biological target and chemical hit after the screen is complete. The methodology has been exemplified for the purine binding proteome (proteins utilizing ATP, NAD, FAD). Screening of an 8000 member library yielded over 1500 unique protein-ligand interactions, which included novel hits for the oncology target Hsp90. The approach, which also provides broad target selectivity information, was used to drive the identification of a potent and orally active Hsp90 inhibitor, SNX-5422, which is currently in phase 1 clinical studies.

► Chemoproteomics was applied to drug discovery targeting the purine binding proteome
► Screening a designed chemical library yielded multiple ligand-protein interactions
► A screening hit for Hsp90 was optimized to the clinical candidate SNX-5422
► The methodology provides a novel strategy for drug discovery