Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S

被引：50

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

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 06期

基金：

中国国家自然科学基金;

关键词：

EGFR; mutant; inhibitor; C797S; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; MUTATIONS; GEFITINIB; AZD9291;

D O I：

10.1021/acsmedchemlett.8b00564

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：869 / 873

页数：9

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