Proteome-wide Identification of Off-Targets of a Potent EGFR<sup>L858R/T790M</sup> Mutant Inhibitor.
Lyu P, Jiang K, Zhou Y, Hu J, Chang Y, Zhang Z, Huang M, Zhang ZM, Ding K, Hao P, Lin L, Li Z.
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<sup>L858R/T790M</sup> (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.