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

Abstract

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 (IC₅₀) 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).

We have developed a novel EGFR inhibitor YL143, which displayed highly potent, specific EGFRT790M inhibition and improved the oral bioavailability. YL143 also exhibited antiproliferative effect in H1975 cells and animal xenografts. YL143 may serve as a new promising lead compound for drug discovery overcoming the acquired resistance of patients with NSCLC without adverse toxicities.

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