Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFRDel19/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 IC₅₀ 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 IC₅₀ 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.

EGFR inhibitor; EGFRDel19/T790M/C797S; NSCLC; antitumor activity.