Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer

Molecules. 2023 Feb 21;28(5):2006. doi: 10.3390/molecules28052006.

Abstract

ALK-positive NSCLC coexisting with EGFR mutations is a frequently occurring clinical phenomenon. Targeting ALK and EGFR simultaneously may be an effective way to treat these cancer patients. In this study, we designed and synthesized ten new dual-target EGFR/ALK inhibitors. Among them, the optimal compound 9j exhibited good activity with IC50 values of 0.07829 ± 0.03 μM and 0.08183 ± 0.02 μM against H1975 (EGFR T790M/L858R) and H2228 (EML4-ALK) cells, respectively. Immunofluorescence assays indicated that the compound could simultaneously inhibit the expression of phosphorylated EGFR and ALK proteins. A kinase assay demonstrated that compound 9j could inhibit both EGFR and ALK kinases; thus, exerting an antitumor effect. Additionally, compound 9j induced apoptosis in a dose-dependent manner and inhibited the invasion and migration of tumor cells. All of these results indicate that 9j is worthy of further study.

Keywords: ALK; EGFR; kinase inhibitor; non-small-cell lung cancer (NSCLC); therapeutic strategy.

MeSH terms

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

Substances

  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Protein Kinase Inhibitors
  • Antineoplastic Agents
  • EGFR protein, human