文献类型：期刊文献

英文题名：Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S

作者：Li, Qiannan[1];Zhang, Tao[2];Li, Shiliang[1];Tong, Linjiang[2];Li, Junyu[1];Su, Zhicheng[1];Feng, Fang[2];Sun, Deheng[1];Tong, Yi[1];Wang, Xia[1];Zhao, Zhenjiang[1];Zhu, Lili[1];Ding, Jian[2];Li, Honglin[1];Xie, Hua[2];Xu, Yufang[1]

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

年份：2019

卷号：10

期号：6

起止页码：869

外文期刊名：ACS MEDICINAL CHEMISTRY LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000471834600007)】；

基金：This work was supported by the National Key Research and Development Program [2016YFA0502304 to H.L.]; the National Natural Science Foundation of China (grant 81825020 to H.L., 81803437 to S.L.); the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (Number: 2018ZX09711002); and Fundamental Research Funds for the Central Universities, Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No.U1501501. S.L. is sponsored by the Shanghai Sailing Program (No. 18YF1405100). H.L. is sponsored by the National Program for Special Support of Eminent Professionals and the National Program for Support of Top-notch Young Professionals.

语种：英文

外文关键词：EGFR; mutant; inhibitor; C797S

摘要：In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFR(L858R/T790M/C797S). One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFR(L8S8R/T790M/C797S) with an IC50 value of 2.2 nM. Cell proliferation assays showed that 25g effectively and selectively inhibited the growth of EGFR(L858R/T790M/C797S)-dependent cells. This series of compounds, which occupy both the ATP binding site and the allosteric site of the EGFR kinase, may serve as a basis for the development of fourth-generation EGFR inhibitors for L858R/T790M/C797S mutants.