Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines

Bioorg Med Chem Lett. 2024 Nov 15:113:129961. doi: 10.1016/j.bmcl.2024.129961. Epub 2024 Sep 14.

Abstract

The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFRdel19/T790M/C797S). Compound b demonstrated slightly improved inhibition activity against PC-9del19/T790M/C797S (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.

Keywords: 4th-gen EGFR TKIs; ATP depletion; C797S mutation; NSCLC; Polyamines; Quinazoline derivatives.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • ErbB Receptors* / antagonists & inhibitors
  • ErbB Receptors* / metabolism
  • Humans
  • Molecular Structure
  • Polyamines* / chemistry
  • Polyamines* / pharmacology
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Structure-Activity Relationship
  • Tyrosine Kinase Inhibitors

Substances

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