文献类型：期刊文献

英文题名：Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors

作者：Hao, Yongjia[1];Lyu, Jiankun[1];Qu, Rong[2,3];Sun, Deheng[1];Zhao, Zhenjiang[1];Chen, Zhuo[1];Ding, Jian[2];Xie, Hua[2];Xu, Yufang[1];Li, Honglin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[3]Univ Chinese Acad Sci, Beijing 100049, Peoples R China

年份：2017

卷号：7

外文期刊名：SCIENTIFIC REPORTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000403650300073)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304) (H.L.), the National Natural Science Foundation of China (Grants 21302054 and 81230076) (Z.C., H.L.), the Shanghai Committee of Science and Technology (Grant 14431902100) (Y.X.), H.L. is also sponsored by Specialized Research Fund for the Doctoral Program of Higher Education (Grant 20130074110004). H.X. is supported by "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences (Grant XDA12020209).

语种：英文

摘要：Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3] oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR(L858R/T790M) (H1975 cell lines) over EGFR(WT) (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR(L858R/T790M). These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.