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

Nur Farisya Shamsudin, Sze Wei Leong, Andreas Koeberle, Utid Suriya, Thanyada Rungrotmongkol, Suet Lin Chia, Muhammad Taher, Muhammad Salahuddin Haris, Hussah Abdullah Alshwyeh, Areej A. Alosaimi, Ahmed Mediani, Muna Abdulsalam Ilowefah, Deri Islami, Siti Munirah Mohd Faudzi, Mohd Fadhlizil Fasihi Mohd Aluwi, Lam Kok Wai, Kamal Rullah

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1499-1517
Number of pages19
JournalFuture Medicinal Chemistry
Volume16
Issue number15
DOIs
Publication statusPublished - 2024
Externally publishedYes

Keywords

  • ULK1 inhibitor
  • apoptosis
  • autophagy
  • chromone
  • colon cancer

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