A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer

Future Med Chem. 2024 Aug 2;16(15):1499-1517. doi: 10.1080/17568919.2024.2363668. Epub 2024 Jul 1.

Abstract

Aim: Chromones are promising for anticancer drug development.Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC50 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1.Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.

Keywords: ULK1 inhibitor; apoptosis; autophagy; chromone; colon cancer.

Plain language summary

[Box: see text].

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis* / drug effects
  • Autophagy* / drug effects
  • Autophagy-Related Protein-1 Homolog* / antagonists & inhibitors
  • Autophagy-Related Protein-1 Homolog* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromones* / chemical synthesis
  • Chromones* / chemistry
  • Chromones* / pharmacology
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / metabolism
  • Colonic Neoplasms* / pathology
  • Drug Screening Assays, Antitumor
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Molecular Docking Simulation*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship

Substances

  • Autophagy-Related Protein-1 Homolog
  • Chromones
  • ULK1 protein, human
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Reactive Oxygen Species