Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFRL858R/T790M inhibitors

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR(L858R/T790M) inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC50 value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC50 value of 0.008 mu M and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

A new series of EGFR (L858R/T790M) inhibitors were designed and synthesized, with compound 8l showing excellent anti-tumor activity, strong kinase inhibitory effect against EGFR double mutation, and low toxicity towards non-tumorigenic cells.