YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR L858R, T790M ‐mutant resistance in vitro and in vivo

摘要

YL143 was identified as a novel wild‐type sparing EGFR T790M inhibitor with good pharmacokinetic properties. It potently suppresses EGFR L858R/T790M with an 50% inhibitory concentration (IC 50 ) value of 2.0?±?0.3?nmol/L, but is approximately 92‐folds less potent against EGFR WT kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFR L858R/T790M mutation at 30?nmol/L. It also exhibits acceptable pharmacokinetics (PK) parameters with an oral bioavailability value of 25.0% after oral administration in rats and exhibits promising antitumor efficacy in a gefitinib‐resistant human H1975 xenografted model after oral administration of 30?mg/kg/day. These data supported that YL143 could be a promising lead compound for overcoming clinical EGFR T790M resistance of patients with non‐small‐cell lung cancer (NSCLC).