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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 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).

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC5911580 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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YL143, a novel mutant selective irreversible EGFR inhibitor, overcomes EGFR<sup>L858R, T790M</sup> -mutant resistance in vitro and in vivo.

Zhang Zhang Z   Zou Jian J   Yu Lei L   Luo Jinfeng J   Li Yan Y   Tu Zhengchao Z   Ren Xiaomei X   Wei Hongcheng H   Song Liyan L   Lu Xiaoyun X   Ding Ke K  

Cancer medicine 20180313 4

YL143 was identified as a novel wild-type sparing EGFR<sup>T790M</sup> inhibitor with good pharmacokinetic properties. It potently suppresses EGFR<sup>L858R/T790M</sup> with an 50% inhibitory concentration (IC<sub>50</sub> ) value of 2.0 ± 0.3 nmol/L, but is approximately 92-folds less potent against EGFR<sup>WT</sup> kinase. YL143 suppresses cellular proliferation and induces G0/G1 phase arrest and apoptosis in H1975 cells with EGFR<sup>L858R/T790M</sup> mutation at 30 nmol/L. It also exhibits  ...[more]

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