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

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2205605. doi: 10.1080/14756366.2023.2205605.

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 EGFRL858R/T790M and more than 76-fold selectivity for EGFRWT. 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 EGFRL858R/T790M by cell migration assay and apoptosis assay.

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

MeSH terms

  • Antineoplastic Agents*
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • ErbB Receptors / metabolism
  • Humans
  • Lung Neoplasms* / drug therapy
  • Mutation
  • Protein Kinase Inhibitors
  • Pyrimidines / pharmacology

Substances

  • ErbB Receptors
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Antineoplastic Agents
  • EGFR protein, human

Grants and 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.