2. Academic Validation
  3. Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents

Design, synthesis and biological evaluation of glucose metabolism inhibitors as anticancer agents

  • Bioorg Chem. 2024 Jul 25:151:107665. doi: 10.1016/j.bioorg.2024.107665.
Yao Cheng 1,  John Patrick Jones 1,  Tsz Tin Yu 1,  Ellen M Olzomer 2,  Jacky Su 1,  Alice Katen 1,  David StC Black 1,  Gene Hart-Smith 3,  Elizabeth S Childress 4,  Marc R Wilkins 2,  Isabel A Mateos 2,  Webster L Santos 4,  Kyle L Hoehn 2,  Frances L Byrne 5,  Naresh Kumar 6
Affiliations

Affiliations

  • 1 School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
  • 2 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
  • 3 Australian Proteome Analysis Facility, Macquarie University, Macquarie Park, NSW 2109, Australia.
  • 4 Department of Chemistry and VT Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA.
  • 5 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: frances.byrne@unsw.edu.au.
  • 6 School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: n.kumar@unsw.edu.au.
PMID: 39094508 DOI: 10.1016/j.bioorg.2024.107665
Abstract

Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting Cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A Cancer cells with an IC50 of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice.

Keywords

Anticancer; Glycolysis; Naphthoimidazole; Pharmacokinetic; Pull-down assay.

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