Cancer Centre, Faculty of Health Sciences, University of Macau, Macau.
Cancer Centre, Faculty of Health Sciences, University of Macau, Macau.
Drug Discov Today. 2022 Sep;27(9):2574-2585. doi: 10.1016/j.drudis.2022.05.017. Epub 2022 May 21.
As one of the well-known hallmarks of cancer malignancy, most proliferating cancer cells exhibit enhanced rates of glycolysis. Hexokinase 2 (HK2) is the rate-limiting enzyme catalyzing the first step of glycolysis, and is often overexpressed in most cancer cells. Thus, targeting HK2 appears to be a promising anticancer therapy. However, selective inhibition of HK2 and the polar nature of the target site remain challenges to the development of small-molecule inhibitors, which could be addressed by targeting unique domains of HK2, such as its N-terminal domain. Here, we review different target-inhibitor binding modes and the associated pharmacological effects, which would be informative for rational molecular design. We also highlight further perspectives and strategies to develop novel HK2 inhibitors for cancer therapy.
作为癌症恶性的一个著名特征，大多数增殖的癌细胞表现出增强的糖酵解速率。己糖激酶 2（HK2）是催化糖酵解第一步的限速酶，并且通常在大多数癌细胞中过表达。因此，靶向 HK2 似乎是一种有前途的抗癌疗法。然而，HK2 的选择性抑制和靶位的极性性质仍然是小分子抑制剂发展的挑战，这可以通过靶向 HK2 的独特结构域来解决，例如其 N 端结构域。在这里，我们综述了不同的靶标-抑制剂结合模式及其相关的药理作用，这对于合理的分子设计具有指导意义。我们还强调了进一步的观点和策略，以开发用于癌症治疗的新型 HK2 抑制剂。
