Open AccessYL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR L858R, T790M ‐mutant resistance in vitro and in vivo
Author(s) -
Zhang Zhang,
Zou Jian,
Yu Lei,
Luo Jinfeng,
Li Yan,
Tu Zhengchao,
Ren Xiaomei,
Wei Hongcheng,
Song Liyan,
Lu Xiaoyun,
Ding Ke
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1392
Subject(s) - t790m , pharmacokinetics , gefitinib , in vivo , pharmacology , bioavailability , ic50 , mutant , in vitro , apoptosis , oral administration , medicine , chemistry , epidermal growth factor receptor , cancer research , cancer , biology , biochemistry , microbiology and biotechnology , gene
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).