Structure-based design and synthesis of 2,4-diaminopyrimidines as EGFR L858R/T790M selective inhibitors for NSCLC

被引：19

作者：

Chen, Lingfeng ^{[1
,2
]}

Fu, Weitao ^{[2
]}

Feng, Chen ^{[2
]}

Qu, Rong ^{[3
]}

Tong, Linjiang ^{[3
]}

Zheng, Lulu ^{[2
]}

Fang, Bo ^{[2
]}

Qiu, Yinda ^{[2
]}

Hu, Jie ^{[2
]}

Cai, Yuepiao ^{[2
]}

Feng, Jianpeng ^{[2
]}

Xie, Hua ^{[3
]}

Ding, Jian ^{[3
]}

Liu, Zhiguo ^{[2
]}

Liang, Guang ^{[1
,2
]}

机构：

[1] Nanjing Univ Sci & Technol, Sch Chem Engn, Nanjing 210094, Jiangsu, Peoples R China

[2] Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou 325035, Zhejiang, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 140卷

关键词：

Epidermal growth factor receptor; Tyrosine kinase inhibitors; Non-small cell lung cancer; T790M; Mutant-selective; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; CELL LUNG-CANCER; T790M-MEDIATED RESISTANCE; IRREVERSIBLE INHIBITOR; COVALENT INHIBITORS; DISCOVERY; POTENT; MUTATION; AZD9291;

D O I：

10.1016/j.ejmech.2017.08.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Mutated epidermal growth factor receptor (EGFR) is a major driver of non-small cell lung cancer (NSCLC). The EGFR(T790m) secondary mutation has become a leading cause of clinically-acquired resistance to gefitinib and erlotinib. Herein, we present a structure-based design approach to increase the potency and selectivity of the previously reported reversible EGFR inhibitor 7, at the kinase and cellular levels. Three step structure-activity relationship exploration led to promising compounds 19e and 19h with unique chemical structure and binding mode from the other third-generation tyrosine kinase inhibitors. In a human NSCLC xenograft model, 19e and 19h exhibited dose-dependent tumor growth suppression without toxicity. These selective inhibitors are promising drug candidates for EGFR(T790M)-driven NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：510 / 527

页数：18

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