Design, Synthesis, and Biological Evaluation of 5‐Trifluoromethylpyrimidine Derivatives as EGFR Inhibitors Against T790M Mutation

ABSTRACT Non‐small cell lung cancer (NSCLC) is currently the main type of lung cancer. Nevertheless, the existing drugs employed for NSCLC treatment tend to induce drug resistance after a certain duration of use. Consequently, it is essential to engage in continuous development of novel drugs to address clinical demands. In this study, a series of 5‐trifluoromethylpyrimidine derivatives were designed and synthesized, and the IC 50 values of synthesized compounds were tested against NCI‐H1975 cells (L858R/T790M mutation of EGFR) through the MTT method. Among them, compounds 4h, 4i and 4l showed the best activity, with IC 50 values of 0.16, 0.25, and 0.18 μM, respectively, which was superior to the positive control Osimertnib. In addition, further studies indicated that compounds 4h, 4i, and 4l could induce apoptosis of NCI‐H1975 cells and arrest the cells in the G2/M phase. Molecular docking analyses revealed that compounds 4h, 4i, and 4l exhibited robust binding affinity toward EGFR. Collectively, these findings indicated that the aforementioned compounds held promising potential as EGFR‐targeting agents capable of surmounting the T790M mutation‐mediated drug resistance.