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 μM 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.

Anti-proliferation; Anti-tumor efficacy in vivo; Epidermal growth factor receptor; L858R/T790M double mutants; Non-small cell lung cancer (NSCLC).