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

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 (IC50 = 5.192 nM), 10j (IC50 = 10.35 nM), and 10o (IC50 = 0.3524 nM) exhibited higher potencies against EGFRT790/M/L858R compared to the known EGFR inhibitor AZD-9291 (IC50 = 20.80 nM). Moreover, 10j showed moderate activity against H1975 cells transfected with the EGFRT790M/L858R mutant, with an IC50 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, IC50 > 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.