Unlocking the potential of HK2 in cancer metabolism and therapeutics.

Glycolysis is a tightly regulated process in which several enzymes, such as hexokinases (HKs), play crucial roles. Cancer cells are characterized by specific expression levels of several isoenzymes in different metabolic pathways and these fea-tures offer possibilities for therapeutic interventions. Overexpression of HKs (mostly of the HK2 isoform) has been con-sistently reported in numerous types of cancer. Moreover, deletion of HK2 has been shown to decrease cancer cell prolif-eration without explicit side effects in animal models, which suggests that targeting HK2 is a viable strategy for cancer therapy. HK2 inhibition causes a substantial decrease of glycolysis that affects multiple pathways of central metabolism and also destabilizes the mitochondrial outer membrane, ultimately enhancing cell death. Although glycolysis inhibition has met limited success, partly due to low selectivity for specific isoforms and excessive side effects of the reported HK inhibitors, there is ample ground for progress. The current review is focused on HK2 inhibition, envisaging the development of potent and selective anticancer agents. The information on function, expression, and activity of HKs is presented, along with their structures, known inhibitors, and reported effects of HK2 ablation/inhibition. The structural features of the different isozymes are discussed, aiming to stimulate a more rational approach to the design of selective HK2 inhibitors with appropriate drug-like properties. Particu-lar attention is dedicated to a structural and sequence comparison of the structurally similar HK1 and HK2 isoforms, aim-ing to unveil differences that could be explored therapeutically. Finally, several additional catalytic- and non-catalytic roles on different pathways and diseases, recently attributed to HK2, are reviewed and their implications are briefly dis-cussed.