Design, synthesis and biological evaluation of 2-amino-4-(1,2,4-triazol)pyridine derivatives as potent EGFR inhibitors to overcome TKI-resistance

被引：19

作者：

Yang, Haikui ^{[1
]}

Yan, Ruohong ^{[1
]}

Jiang, Ying ^{[1
]}

Yang, Zichao ^{[1
]}

Zhang, Xingmei ^{[2
]}

Zhou, Mingfeng ^{[1
]}

Wu, Xiaoyun ^{[1
]}

Zhang, Tingting ^{[1
]}

Zhang, Jiajie ^{[1
]}

机构：

[1] Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Peoples R China

[2] Southern Med Univ, Sch Basic Med Sci, Dept Neurobiol, Guangdong Prov Key Lab Psychiat Disorders, Guangzhou 510515, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 187卷

基金：

中国国家自然科学基金;

关键词：

EGFR inhibitor; 2-amino-4-(1,2,4-triazol)pyridine; EGFR(T790M); EGFRvIII; TKI-resistance; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; PAN-ERBB INHIBITOR; PHASE-II; BRAIN; MUTATIONS; GEFITINIB; SURVIVAL; AFATINIB; AZD9291;

D O I：

10.1016/j.ejmech.2019.111966

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of 2-amino-4-(1,2,4-triazol)pyridine derivatives were designed and synthesized as potent epidermal growth factor receptor inhibitors. In particular, compound 10c exhibited significant inhibitory against EGFR(L858R/T790M), and also displayed potent anti-proliferative activity against non-small cell lung cancer cell line H1975. Besides, compound 10j showed potent inhibitory activity against glioblastoma cell line U87-EGFRvIII, which was at least 3-fold more potent than Osimertinib and 25-fold superior to Lazertinib. Moreover, molecular modeling and molecular dynamics simulations disclosed the binding model of the most active compound to the domain of EGFR. This contribution provides 2-amino-4-(1,2,4-triazol)pyridines as a new scaffold for EGFR(T790M) and/or EGFRvIII inhibitor. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页数：13