文献类型：期刊文献

英文题名：Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation

作者：Su, Zhicheng[1];Yang, Tingyuan[1];Wang, Jie[1];Lai, Mengzhen[2,4];Tong, Linjiang[2];Wumaier, Gulinuer[3];Chen, Zhuo[1];Li, Shengqing[3];Li, Honglin[1];Xie, Hua[2];Zhao, Zhenjiang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 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]Fudan Univ, Huashan Hosp, Dept Pulm & Crit Care Med, Shanghai, Peoples R China;[4]Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China

年份：2020

卷号：30

期号：16

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000551073500007)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant 2016YFA0502304), the National Natural Science Foundation of China (grant 81825020), the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (No. 2018ZX09711002), the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No. U1501501. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：EGFR; NSCLC; C797S

摘要：The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR(19D/T790M/C797S) mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR(19D/T790M/C797S) (IC50 = 15.3 nM) and good selectivity over EGFR WT (IC50 > 1000 nM), L858R/T790M (IC50, 156.6 nM) and L858R/T790M/C797S (IC50, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR(19D/T790M/C797S) cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR(19D/T790M/C797S) inhibitors.