YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFRL858R, T790M‐mutant resistance in vitro and in vivo

Abstract

Abstract YL143 was identified as a novel wild‐type sparing EGFRT790M inhibitor with good pharmacokinetic properties. It potently suppresses EGFRL858R/T790M with an 50% inhibitory concentration (IC50) value of 2.0 ± 0.3 nmol/L, but is approximately 92‐folds less potent against EGFRWT kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFRL858R/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 EGFRT790M resistance of patients with non‐small‐cell lung cancer (NSCLC).

Keywords

• EGFR inhibitor
• lung cancer
• pharmacokinetic
• selectively
• T790M mutation