Targeting Hexokinase 2 for Cancer Therapy: Advances, Limitations, and Emerging Opportunities in Inhibitors and Degraders

Abstract

Hexokinase 2 (HK2) is an important target in cancer metabolism because it supports both glycolytic flux and mitochondria-associated survival signaling. In recent years, multiple HK2-directed strategies have emerged, including active-site inhibitors, repurposed scaffolds, electrophilic glycolysis blockers, and targeted protein degraders. Although several compounds have shown promising antitumor activity in preclinical models, their translation has been constrained by high structural similarity to HK1, the polarity and exposure liabilities of glucose-mimetic chemotypes, and, in some cases, limited mechanistic specificity. This review summarizes recent progress in HK2 inhibitor and degrader discovery, highlighting representative chemotypes, structure–activity relationships, pharmacological properties, and translational considerations. We also discuss opportunities for future development, including isoform-selective design, disruption of HK2–mitochondrial interactions, improved delivery strategies, and rational combination approaches. Overall, HK2 remains a promising but pharmacologically challenging target for cancer therapy.