Proteome-wide Identification of Off-Targets of a Potent EGFR^L858R/T790M Mutant Inhibitor.

ABSTRACT: Target identification is an essential step in drug discovery. It facilitates an understanding of drug action and potential toxicities and offers opportunities to repurpose drug candidates. HP-1, a potent EGFR^L858R/T790M (epidermal growth factor receptor) mutant inhibitor, was developed by the group in an effort to treat acquired resistance in nonsmall cell lung cancer (NSCLC), but its cellular off-targets were not identified. An activity-based probe, HJ-1, was created followed by chemical proteomics and bioimaging studies. A total of 13 protein hits, including EGFR and NT5DC1, were identified by pull-down/LC-MS. Subsequent validation experiments indicated the involvement of a major off-target, NT5DC1, in the biological function of HP-1.

SUBMITTER: Lyu P 

PROVIDER: S-EPMC8842118 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature