Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFR(L858R/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 IC(50) 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 IC(50) 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.