T790米
化学
药代动力学
铅化合物
生物利用度
药理学
MAPK/ERK通路
IC50型
激酶
口服
突变体
结构-活动关系
药品
体外
生物化学
受体
表皮生长因子受体
基因
医学
吉非替尼
作者
Lei Yu,Ming Huang,Tianfeng Xu,Linjiang Tong,Xiao-E Yan,Zhang Zhang,Yong Xu,Cai‐Hong Yun,Hua Xie,Ke Ding,Xiaoyun Lu
标识
DOI:10.1016/j.ejmech.2016.12.006
摘要
Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790M inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790M kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.
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