2. Academic Validation
  3. Combinatorial library design approach identifies a novel benzothiazole-based hexokinase 2 inhibitor with anti-tumor efficacy in oral squamous cell carcinoma

Combinatorial library design approach identifies a novel benzothiazole-based hexokinase 2 inhibitor with anti-tumor efficacy in oral squamous cell carcinoma

  • Eur J Med Chem. 2025 Dec 17:304:118483. doi: 10.1016/j.ejmech.2025.118483.
Purbali Chakraborty 1,  Shouvik Bhuin 2,  Syeda Lubna 3,  Ashna Fathima 3,  K Deepika 4,  Pruthvi Gudipati 4,  Manab Chakravarty 2,  Trinath Jamma 5,  Perumal Yogeeswari 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad, 500078, Telangana, India; Cancer Research Group, Centre for Human Diseases Research, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad, 500078, Telangana, India.
  • 2 Department of Chemistry, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad, 500078, Telangana, India.
  • 3 Department of Biological Sciences, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad, 500078, Telangana, India.
  • 4 Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad, 500078, Telangana, India.
  • 5 Department of Biological Sciences, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad, 500078, Telangana, India; Cancer Research Group, Centre for Human Diseases Research, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad, 500078, Telangana, India. Electronic address: [email protected].
  • 6 Department of Pharmacy, Birla Institute of Technology and Science, Pilani Hyderabad Campus, Hyderabad, 500078, Telangana, India; Cancer Research Group, Centre for Human Diseases Research, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Hyderabad, 500078, Telangana, India. Electronic address: [email protected].
PMID: 41455280 DOI: 10.1016/j.ejmech.2025.118483
Abstract

Hexokinase 2 (HK2), a pivotal enzyme in glycolysis, is frequently overexpressed in oral squamous cell carcinoma (OSCC), contributing to tumor proliferation, survival, and metabolic adaptation. Targeting HK2 offers a promising therapeutic strategy due to its involvement in tumor invasion, Autophagy, and immune evasion. While early HK2 inhibitors like 2-Deoxy-d-glucose (2-DG), and 3-Bromo pyruvic acid (3-BP) showed potential, their clinical utility was limited by off-target effects. Recent advancements in virtual screening and structure-based drug design have identified novel pharmacophores, including a novel benzothiazole (BTZ)-based inhibitor compound H2, which was previously identified by our team. Yet challenges remain in achieving selective and potent inhibition. In this study, we employed combinatorial library design to generate a diverse library of chemical compounds based on the lead BTZ pharmacophore. These compounds were screened for HK2 inhibitory activity, followed by structural optimization to enhance selectivity and efficacy in in vitro and in vivo models of OSCC. Our findings identified a novel BTZ-based HK2 inhibitor compound 12 with HK2 IC50 of 56 nM and a ∼50-fold improvement in HK2 inhibitory potency over initial lead compound H2, that not only exhibits potent anti-cancer activity but also induces Mitophagy, providing a new mechanism for OSCC therapy.

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