Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis

Area of Science:

• Biochemistry
• Oncology
• Pharmacology

Background:

• Accelerated glucose metabolism is a hallmark of cancer cells.
• Hexokinase 2 (HK2) is a key enzyme in glucose metabolism, overexpressed in many cancers, making it a therapeutic target.

Purpose of the Study:

• To report a novel selective HK2 inhibitor, Benitrobenrazide (BNBZ).
• To evaluate the efficacy of BNBZ in inhibiting cancer cell glycolysis, proliferation, and tumor growth in vitro and in vivo.

Main Methods:

• In vitro assays to assess BNBZ's binding to HK2, induction of apoptosis, and inhibition of proliferation and glycolysis in cancer cells.
• HK2 knockdown/knockout experiments to determine sensitivity to BNBZ.
• In vivo studies using SW1990 and SW480 xenograft models to evaluate tumor growth inhibition after oral administration of BNBZ.

Main Results:

• BNBZ demonstrated nanomolar inhibitory potency, directly binding to HK2.
• BNBZ effectively inhibited glycolysis and proliferation in HK2-overexpressing cancer cells, with reduced sensitivity observed upon HK2 knockdown/knockout.
• Oral administration of BNBZ significantly suppressed tumor growth in preclinical xenograft models.

Conclusions:

• BNBZ is a potent and selective small-molecule inhibitor of HK2.
• BNBZ effectively targets cancer cell glycolysis and proliferation both in vitro and in vivo.
• BNBZ shows potential as a novel therapeutic candidate for HK2-driven cancers.