CHMFL-EGFR-202 is a potent, irreversible inhibitor of epidermal growth factor receptor ( EGFR ) mutant kinase , with IC 50 s of 5.3 nM and 8.3 nM for drug-resistant mutant EGFR T790M and WT EGFR kinases, respectively. CHMFL-EGFR-202 exhibits ~10-fold selectivity for EGFR L858R/T790M against the EGFR wild-type in cells. CHMFL-EGFR-202 adopts a covalent “DFG-in-C-helix-out” inactive binding conformation with EGFR , with strong antiproliferative effects against EGFR mutant-driven nonsmall-cell lung cancer (NSCLC) cell lines.