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ID: ALA5034051
Journal: ACS Med Chem Lett
Title: Proteome-wide Identification of Off-Targets of a Potent EGFRL858R/T790M Mutant Inhibitor.
Authors: Lyu P, Jiang K, Zhou Y, Hu J, Chang Y, Zhang Z, Huang M, Zhang ZM, Ding K, Hao P, Lin L, Li Z.
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 EGFRL858R/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.
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