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

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. Image 1 • 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. [ABSTRACT FROM AUTHOR]