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

Shamsudin, Nur Farisya and Leong, Sze-Wei and Koeberle, Andreas and Suriya, Utid and Rungrotmongkol, Thanyada and Chia, Suet Lin and Taher, Muhammad and Haris @ Harith, Muhammad Salahuddin and Alshwyeh, Hussah Abdullah and Alosaimi, Areej A and Mediani, Ahmed and Ilowefah, Muna Abdulsalam and Islami, Deri and Mohd Faudzi, Siti Munirah and Mohd Aluwi, Mohd Fadhlizil Fasihi and Wai, Lam Kok and Rullah, Kamal (2024) A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer. Future Medicinal Chemistry, 16 (15). pp. 1499-1517. ISSN 1756-8919 E-ISSN 1756-8927

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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.

Item Type:	Article (Journal)
Uncontrolled Keywords:	apoptosis, autophagy, chromone, colon cancer, ULK1 inhibitor
Subjects:	R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Pharmacy Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry
Depositing User:	Dr Kamal Rullah
Date Deposited:	30 Oct 2024 18:31
Last Modified:	30 Oct 2024 18:31
URI:	http://irep.iium.edu.my/id/eprint/115427

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