Noncovalent EGFR T790M/L858R inhibitors based on diphenylpyrimidine scaffold: Design, synthesis, and bioactivity evaluation for the treatment of NSCLC.

A series of diphenylpyrimidine derivatives bearing a hydroxamic acid group was designed and synthesized as noncovalent EGFRT790M/L858R inhibitors to improve the biological activity and selectivity. One of the most promising compound 9d effectively interfered EGFRT790M/L858R binding with ATP and suppressed the proliferation of H1975 cells with IC 50 values of 1.097 nM and 0.09777 μM, respectively. Moreover, compound 9d also not only exhibited a high selective index of 43.4 for EGFRT790M/L858R over the wild-type and 10.9 for H1975 cells over A431, but also exhibited low toxicity against the normal HBE cells (IC 50 > 20 μΜ). In addition, the action mechanism validated that compound 9d effectively inhibited cell migration and promoted cell apoptosis by blocking cell cycle at G 2 /M stage. Furthermore, the target dose-dependently downregulated the expression of p-EGFR and arrested the activation of downstream Akt and ERK in H1975. All these studies provide important clues for the discovery of potent noncovalent EGFRT790M/L858R inhibitors. [Display omitted] • Potent noncovalent EGFRT790M/L858R inhibitors were designed and synthesized. • The scaffold of the target was diphenylpyrimidine bearing hydroxamic acid group. • 9d interfered EGFRT790M/L858R binding with ATP with IC 50 value of 1.097 nM. • 9d suppressed the proliferation of H1975 cells with IC 50 value of 0.09777 μM. • 9d exhibited low toxicity against the normal HBE cells (IC 50 > 20 μΜ). [ABSTRACT FROM AUTHOR]