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

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

  • Eur J Med Chem. 2020 Feb 1:187:111966. doi: 10.1016/j.ejmech.2019.111966.
Haikui Yang 1,  Ruohong Yan 1,  Ying Jiang 1,  Zichao Yang 1,  Xingmei Zhang 2,  Mingfeng Zhou 1,  Xiaoyun Wu 1,  Tingting Zhang 3,  Jiajie Zhang 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: zhangttgre@163.com.
  • 4 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: zhangjj@smu.edu.cn.
PMID: 31869655 DOI: 10.1016/j.ejmech.2019.111966
Abstract

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 EGFRL858R/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 EGFRT790M and/or EGFRvⅢ inhibitor.

Keywords

2-amino-4-(1,2,4-triazol)pyridine; EGFR inhibitor; EGFR(T790M); EGFRvⅢ; TKI-resistance.

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