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

• Published in: European journal of medicinal chemistry Vol. 187; p. 111966
• Main Authors: Yang, Haikui, Yan, Ruohong, Jiang, Ying, Yang, Zichao, Zhang, Xingmei, Zhou, Mingfeng, Wu, Xiaoyun, Zhang, Tingting, Zhang, Jiajie
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.02.2020
• Subjects: 2-amino-4-(1,2,4-triazol)pyridine; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Design; EGFR inhibitor; EGFRT790M; EGFRv; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; TKI-resistance; 2-amino-4-(1,2,4-triazol)pyridine; EGFRT790M; EGFRv; EGFR inhibitor; SJJHLNSXTOYYJV-UHFFFAOYSA-N; TKI-resistance; EGFR(T790M)
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111966

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. [Display omitted] •Sixteen 2-amino-4-(1,2,4-triazol)pyridine derivatives were designed and synthesized.•Compound 10c exhibited strong inhibitory activities against EGFRL858R/T790M enzyme.•Compound 10j showed potent inhibitory activity against U87-EGFRvIII cell.•Molecular docking and molecular dynamics simulation gave a probable explanation for the activity of 10c.