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.
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页数：13
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