Tuesday, March 20, 2018

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

Zhang Zhang, Jian Zou, Lei Yu  Jinfeng Luo, Yan Li  Zhengchao Tu, Xiaomei Ren  Hongcheng Wei, Liyan Song, Xiaoyun Lu,  Ke Ding

Cancer Medicine, 2018
doi: 10.1002/cam4.1392

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).

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...