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  3. Anti-cancer efficacy of novel lonidamine derivatives: Design, synthesis, in vitro, in vivo, and computational studies targeting hexokinase-2

Anti-cancer efficacy of novel lonidamine derivatives: Design, synthesis, in vitro, in vivo, and computational studies targeting hexokinase-2

  • Eur J Med Chem. 2025 Oct 15:296:117890. doi: 10.1016/j.ejmech.2025.117890.
Ӧzgecan Şavluğ İpek 1,  Bilgesu Onur Sucu 2,  Saba Selvi 3,  Fulya Koksalar Alkan 4,  Büşra Tiryaki 3,  Hilmi Kaan Alkan 4,  Ehsan Sayyah 5,  İlayda Tolu 6,  Mustafa Güzel 7,  Serdar Durdağı 8,  Nuri Öztürk 3,  Hasan Korkaya 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Yildiz Technical University, Davutpasa Campus, Istanbul, Türkiye; Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Istanbul Medipol University, Istanbul, Türkiye.
  • 2 Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Istanbul Medipol University, Istanbul, Türkiye; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul Medipol University, Istanbul, 34810, Türkiye. Electronic address: bsucu@medipol.edu.tr.
  • 3 Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, 41400, Gebze, Türkiye.
  • 4 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC, 723 4100 John R. Street, Detroit, MI, 48201, USA.
  • 5 Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Türkiye; Lab for Innovative Drugs (Lab4IND), Computational Drug Design Center (HITMER), Bahçeşehir University, İstanbul, Türkiye.
  • 6 Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Türkiye.
  • 7 Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Istanbul Medipol University, Istanbul, Türkiye; Istanbul Medipol University, School of Pharmacy, Department of Basic Pharmaceutical Sciences, Beykoz-Istanbul, 34810, Türkiye.
  • 8 Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Türkiye; Lab for Innovative Drugs (Lab4IND), Computational Drug Design Center (HITMER), Bahçeşehir University, İstanbul, Türkiye; Molecular Therapy Lab, Department of Pharmaceutical Chemistry, School of Pharmacy, Bahçeşehir University, Istanbul, Türkiye.
  • 9 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC, 723 4100 John R. Street, Detroit, MI, 48201, USA. Electronic address: hkorkaya@gmail.com.
PMID: 40580639 DOI: 10.1016/j.ejmech.2025.117890
Abstract

Targeting Cancer metabolism has emerged as an attractive therapeutic strategy in recent years, despite the "Warburg effect" phenomenon is discovered about a century ago. Based on this phenomenon, Cancer cells rely on aerobic glycolysis and require higher rate of glucose consumption compared to normal cells and the hexokinase-2 (HK-2) enzyme catalyzes the first step of glucose metabolism. Consistent with the notion, HK-2 expression is highly elevated in most malignancies and that predicts poor survival in patients. Thus, inhibiting the HK-2 activity may be a potential metabolic target for Cancer therapy. Lonidamine (LND) is known as a potential anti-cancer drug through HK-2 inhibition with varying degrees of efficacy in different malignancies. LND shows potency through voltage-dependent anion channel (VDAC) and HK-2 interaction on mitochondrial membrane. Therefore, we designed and synthesized novel LND analogs to improve its molecular and functional properties. We first performed chemical and structural characterization of these LND analogs and tested their biological activity by in vitro assays and in vivo in mouse xenografts. Among these potent HK-2 inhibitors, Compound 20 was identified as a promising lead compound with anti-tumor activity. Based on the three different Cancer cell lines we investigated, our novel LND analogs proved to be more potent than the original molecule. Our findings provide convincing evidence for potentially designing novel analogs of LND and beyond to further improve biological and functional properties existing drugs. Further proven in preclinical settings, our approach may lead to development of more effective therapeutics benefiting patients.

Keywords

Anti-cancer activity; Glycolysis; Hexokinase-2 inhibitors; Lonidamine; Molecular simulations.

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