Design, synthesis, and biological evaluation of pyrido[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives as novel EGFR^L858R/T790M inhibitors

Abstract

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.

Keywords:

• NSCLC
• EGFR mutations
• EGFR^L858R/T790M
• antitumor
• derivatives

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China (Grant No. 81903469), Development Plan for Youth Innovation Team in Higher School of Shandong Province (Grant No. 2022KJ266), and the Graduate Student Research Grant from Weifang Medical University.