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  3. Discovery of New Non-Symmetrical Heterocyclic Pentanoid Derivatives Targeting Metastatic Triple-Negative Breast Cancer

Discovery of New Non-Symmetrical Heterocyclic Pentanoid Derivatives Targeting Metastatic Triple-Negative Breast Cancer

  • Bioorg Med Chem Lett. 2025 Aug 1:123:130232. doi: 10.1016/j.bmcl.2025.130232.
Poh Yen Khor 1,  Johnson Stanslas 2,  Nurulfazlina Edayah Rasol 3,  Kok Meng Chan 4,  Phooi Yan Mock 5,  Kok Wai Lam 6
Affiliations

Affiliations

  • 1 Faculty Pharmacy and Health Sciences, Universiti Kuala Lumpur, Royal College of Medicine Perak, 30450 Ipoh, Perak, Malaysia. Electronic address: pykhor@unikl.edu.my.
  • 2 Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia.
  • 3 Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia; Faculty of Applied Sciences, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia.
  • 4 Center for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
  • 5 Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia.
  • 6 Drugs and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia. Electronic address: david_lam@ukm.edu.my.
PMID: 40209916 DOI: 10.1016/j.bmcl.2025.130232
Abstract

This study describes the synthesis and structure-activity relationship (SAR) analysis of non- symmetrical heterocyclic pentanoid derivative as potential anti-cancer agents. The lead compound, 5d, exhibited potent (IC50 = 0.38 ± 0.05 μM) and selective (Selectivity Index: 2-9) growth inhibitory effects on the metastatic triple-negative breast Cancer (TNBC) cells. Mechanistic studies revealed that 5d attenuates proteasomal degradation activity via the ubiquitin-proteasome pathway, leading to G2/M phase cell cycle arrest and the induction of apoptotic cell death.

Keywords

Anti-cancer; Proteasome; Ubiquitinated proteasome pathway.

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