Target identification by small-molecule labeling in live cells

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a robust proteomics approach to identify targets of small-molecule compounds and drugs in live cells. Phenotypic screens are commonly used to identify novel bioactive small-molecule probes and develop new therapeutic approaches. The major bottleneck in forward chemical-genomics screens is target identification and validation of novel small-molecule probes. Strikingly, targets are still unknown for many FDA-approved drugs and small-molecule tool compounds. Identifying both the therapeutic targets and off targets allows optimization of a compound's selectivity and should decrease potential side effects in the eventual drug. Our proposal describes a novel strategy to use small-molecule inhibitors as in vivo targeting moieties to biotinylate their molecular targets and their protein complexes for proteomic identification. This novel approach is distinct from traditional biochemical approaches and may allow the identification of much weaker affinity binders and higher order protein-protein interactions. As our approach explores spatial relationships in multi-protein complexes when a small-molecule probe is bound to its protein target, it may provide a novel perspective to characterize the small molecule's mechanisms of action.