Novel anilinopyrimidine derivatives as potential EGFRT790M/C797S Inhibitors: Design, Synthesis, biological activity study

Abstract

EGFRT790M/C797S is an important target for the development of new generation of EGFR kinase inhibitors without drug resistance. In this work, a series of anilinopyrimidine derivatives that targeting EGFRT790M/C797S were designed, synthesized, and evaluated in vitro for the inhibitory effect on triple mutations kinases and cell lines. Based on the pharmacology data, the anilinopyrimidine derivatives showed high inhibitory activity on triple mutations kinases (EGFRdel 18/T790M/C797S and EGFRL858R/T790M/C797S) as well as the cell line Ba/F3 with highly expression of EGFRdel 18/T790M/C797S. In addition, the anilinopyrimidine derivatives had a more than 50-fold selectivity towards EGFRdel 18/T790M/C797S as compared with EGFRWT. In vivo antitumor activity test also indicated that 8j had good pharmacokinetic parameters, low toxicity and better inhibitory activity. Overall, the anilinopyrimidine derivatives could be regarded as promising candidates for the further development of novel EGFRT790M/C797S inhibitors for clinical application.