Insights into the Overcoming EGFRDel19/T790M/C797S Mutation: A Perspective on the 2‐Aryl‐4‐aminothienopyrimidine Backbone

Abstract The epithelial growth factor receptor (EGFR) signaling pathway has been proposed to benefit non‐small cell lung cancer (NSCLC) treatment. In this manuscript, we investigated the modification of 2‐aryl‐4‐aminoquinazoline, the classical backbone of the fourth‐generation EGFR inhibitors, in addition to obtaining a series of novel 2‐aryl‐4‐aminothienopyrimidine derivatives ( A1~A45 ), we also gained further understanding of the modification of this framework. Derivatives were tested for cytotoxicity against cancer cell lines (cervical cancer cell line Hela, lung cancer cell lines A549, H1975, and PC‐9, Ba/F3‐EGFR Del19/T790M/C797S cells, and human normal hepatocytes LO 2 ) as well as for the derivative‘s inhibitory activity against EGFR WT , EGFR L858R/T790M , and EGFR Del19/T790M/C797S kinase inhibitory activities. The results showed that most of the target compounds showed moderate to excellent activity against one or more cancer cell lines. Among them, the antitumor activity (IC 50 ) of the most promising A9 against A549 and H1975 cell lines was 0.77±0.08 μM, 6.90±0.83 μM, respectively. At concentration of 10 μM, A9 can be employed as the fourth‐generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFR Del19/T790M/C797S cells and kinase by 98.90 % and 85.88 %, respectively. Moreover, the tumor‐bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo , with the tumor inhibition rate (TIR) of 55.92 %, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.