Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFRL858R/T790M inhibitors

EGFR mutations have been identified in 20,000 reported NSCLC (non-small cell lung Cancer) samples, and exon 19 deletions and L858R mutations at position 21, known as "classical" mutations, account for 85-90% of the total EGFR (epidermal growth factor receptor) mutations. In this paper, two series of EGFR kinase inhibitors were designed and synthesised. Among them, compound B1 showed an IC₅₀ value of 13 nM for kinase inhibitory activity against EGFR^L858R/T790M and more than 76-fold selectivity for EGFR^WT. Furthermore, in an in vitro anti-tumour activity test, compound B1 showed an effective anti-proliferation activity against H1975 cells with an IC₅₀ value of 0.087 μΜ. We also verified the mechanism of action of compound B1 as a selective inhibitor of EGFR^L858R/T790M by cell migration assay and Apoptosis assay.

EGFR mutations; EGFRL858R/T790M; NSCLC; antitumor; derivatives.