Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFR Del19/T790M/C797S inhibitors for the treatment of non-small cell lung cancer.

Overexpression of the epidermal growth factor receptor (EGFR) has been implicated in the development of non-small-cell lung cancer (NSCLC). Thus, EGFR is an effective drug target for the treatment of NSCLC, and developing fourth-generation EGFR inhibitors to overcome the resistance mediated by T790M/C797S mutations are currently under investigation. In this study, based on the binding model between Angew2017-7634-1 and EGFR T790M/C797S , several series of 2-phenyl-4-aminopyrimidine derivatives were designed and synthesized. The bioactivity of these compounds was evaluated and it is suggested that compound A23 could effectively inhibit the proliferation of Ba/F3-EGFR Del19/T790M/C797S and H1975-EGFR L858R/T790M cells, with an IC 50 of 0.22 ± 0.07 and 0.52 ± 0.03 μM, respectively. Meanwhile, the kinase activity of A23 against EGFR L858R/T790M and EGFR Del19/T790M/C797S was also evaluated, with an IC 50 of 0.33 and 0.133 μM, respectively. Moreover, compound A23 was further evaluated in the H1975 xenograft models with significant in vivo tumor growth inhibitions of 25.5%, which means that A23 could effectively inhibit the growth of tumor cells and promote the death of tumor cells. As a result, A23 could be identified as a novel potential EGFR Del19/T790M/C797S inhibitor.