Design, synthesis, and biological evaluation of hydroxamic acid-substituted 2,4-diaryl aminopyrimidines as potent EGFRT790M/L858R inhibitors for the treatment of NSCLC.

[Display omitted] • Potent covalent EGFRT790M/L858R inhibitors were designed and synthesized. • The scaffold of the target was diphenylpyrimidine bearing hydroxamic acid group. • 10j interfered EGFRT790M/L858R binding with ATP with IC 50 value of 10.35 nM. • 10j suppressed the proliferation of H1975 cells with IC 50 value of 0.2113 μM. • 10j could block the cell cycle of H1975 cell lines at the G2/M stage. • 10j significantly suppressed tumour growth in xenograft mouse model. A series of 2,4-diarylaminopyrimidine derivatives bearing hydrophilic hydroxamic acids were designed and synthesized as potent EGFRT790M/L858R inhibitors. Among the derivatives synthesized, 10c (IC 50 = 5.192 nM), 10j (IC 50 = 10.35 nM), and 10o (IC 50 = 0.3524 nM) exhibited higher potencies against EGFRT790/M/L858R compared to the known EGFR inhibitor AZD-9291 (IC 50 = 20.80 nM). Moreover, 10j showed moderate activity against H1975 cells transfected with the EGFRT790M/L858R mutant, with an IC 50 of 0.2113 μM over A431 (wild-type EGFR, SI = 47.3). In addition, 10j exhibited low toxicity in normal HBE cells (human bronchial epithelial cells, IC 50 > 40 μΜ). Analysis of the mode of action indicated that 10j effectively induced apoptosis in H1975 cells by arresting the cells in the G2/M phase. Compound 10j also demonstrated efficacy in inhibiting tumor growth in a H1975 xenograft mouse model without losing body weight or killing the mice. Taken together, these results suggested that 10j might be a promising candidate for development as a potential treatment for NSCLC harboring the EGFRT790M/L858R mutation. [ABSTRACT FROM AUTHOR]