Abstract：
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.
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.
摘要：
目的Warburg效应是肿瘤的重要代谢特征,己糖激酶是肿瘤代谢过程中糖酵解途径的第一个限速酶。在己糖激酶亚型中，己糖激酶2（HK2）越来越被证明是癌症治疗的关键靶标。本研究通过系统地总结文献和专利中报道的HK2抑制剂的特征，提出了开发HK2抑制剂的挑战和潜在策略。方法在本研究中,我们使用分子对接分析了HK2活性位点，并评估了结构，生化和生理功能，活动,以及使用数据库报道的HK2抑制剂的作用机制(科学，SCIfinder,CNKI,和万方数据)。结果总计,通过检索87篇文章，获得了6种HK2的天然抑制剂，9种HK2的合成抑制剂和3种具有待审HK2抑制作用的化合物。这些抑制剂单独使用时的疗效和特异性差，并且具有许多副作用；因此，迫切需要开发具有改善的活性和高选择性的HK2抑制剂。结论:HK2在抗肿瘤药物开发中备受关注,但是以前的研究大多集中在阐明HK2在致癌作用中的作用机制，而其小分子抑制剂的开发却鲜有报道。在这项研究中,我们分析并说明了具有HK2催化结构域的小分子的共晶结构，以开发高选择性和低毒性的HK2抑制剂。
