T790米
化学
野生型
药理学
IC50型
激酶
突变体
铅化合物
共晶
生物化学
表皮生长因子受体
医学
体外
受体
吉非替尼
分子
有机化学
氢键
基因
作者
Shan Li,Tao Zhang,Sujie Zhu,Chong Lei,Mengzhen Lai,Lijie Peng,Linjiang Tong,Zilu Pang,Xiaoyun Lu,Jian Ding,Xiaomei Ren,Cai‐Hong Yun,Hua Xie,Ke Ding
标识
DOI:10.1021/acsmedchemlett.1c00555
摘要
A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFRT790M/C797S inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFRL858R/T790M/C797S and EGFR19Del/T790M/C797S kinases with IC50 values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFRT790M/C797S mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFRT790M/C797S with a close derivative 18f was solved to provide insight on the inhibitor's binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.
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