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 EGFR inhibitors to improve the biological activity and selectivity. One of the most promising compound 9d effectively interfered EGFR binding with ATP and suppressed the proliferation of H1975 cells with IC 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 EGFR over the wild-type and 10.9 for H1975 cells over A431, but also exhibited low toxicity against the normal HBE cells (IC > 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/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 EGFR inhibitors.