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

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Tumor cells exhibit increased glucose metabolism compared to normal cells.
• Previous research identified compound BH10 as a potent inhibitor of cancer cell proliferation by targeting glucose metabolism.

Purpose of the Study:

• To identify the protein target of BH10.
• To synthesize and evaluate novel BH10 analogues with improved anti-cancer properties.

Main Methods:

• Avidin pull-down assays with biotinylated-BH10 to identify protein targets.
• Synthesis of BH10 analogues incorporating naphthoimidazole and triazole scaffolds.
• In vitro anti-cancer activity assays against HEC1A cancer cells.
• Pharmacokinetic studies in mice.

Main Results:

• Kelch-like ECH-associated protein 1 (Keap1) was identified as a potential protein target of BH10.
• Compound 4d, a novel analogue, demonstrated superior anti-cancer activity against HEC1A cells with an IC50 of 2.60 μM.
• Compound 4d exhibited an extended biological half-life and improved pharmacokinetic profile in mice compared to BH10.

Conclusions:

• Keap1 is a potential therapeutic target for BH10-mediated cancer treatment.
• Compound 4d represents a promising next-generation anti-cancer agent with enhanced efficacy and pharmacokinetics.
• Targeting glucose metabolism via Keap1 inhibition offers a viable strategy for cancer therapy.