Advances in the Study of Hexokinase 2 (HK2) Inhibitors

The Warburg effect is an important metabolic feature of tumours, and hexokinase is the first ratelimiting enzyme of the glycolytic pathway during tumour metabolism. Among hexokinase subtypes, hexokinase 2 (HK2) is increasingly proving to be a key target for cancer treatment. This study presents the challenges and potential strategies for developing HK2 inhibitors by systematically summarising the characteristics of HK2 inhibitors reported in the literature and patents.

In this study, we analysed the HK2 active site using molecular docking and evaluated the structure, biochemical and physiological function, activity, and action mechanism of reported HK2 inhibitors using databases (Science, SCI Finder, CNKI, and WANFANG DATA).

In total, 6 natural inhibitors of HK2, 9 synthetic inhibitors of HK2, and 3 compounds with patent-pending HK2 inhibitory effects were obtained by searching 87 articles. These inhibitors have poor efficacy and specificity when used alone and have numerous side effects; therefore, there is an urgent need to develop HK2 inhibitors with improved activity and high selectivity.

HK2 has received much attention in anticancer drug development, but most previous studies have focused on elucidating the action mechanism of HK2 in carcinogenesis, whereas the development of its small-molecule inhibitors has rarely been reported. In this study, we analysed and illustrated the eutectic structure of small molecules with the catalytic structural domain of HK2 to develop highly selective and low-toxicity HK2 inhibitors.