Abstract：
Histone methyltransferases (HMTs) play a critical role in gene post-translational regulation and diverse physiological processes, and are implicated in a plethora of human diseases, especially cancer. Increasing evidences demonstrate that HMTs may serve as a potential therapeutic target for cancer treatment. Thus, the development of HMTs inhibitor have been pursued with steadily increasing interest over the past decade. However, the disadvantages such as insufficient clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of conventional HMT inhibitors. New technologies and methods are imperative to enhance the anticancer activity of HMT inhibitors. In this review, we first review the structure and biological functions of the several essential HMTs, such as EZH2, G9a, PRMT5, and DOT1L. The internal relationship between these HMTs and cancer is also expounded. Next, we mainly focus on the latest progress in the development of HMT modulators encompassing dual-target inhibitors, targeted protein degraders and covalent inhibitors from perspectives such as rational design, pharmacodynamics, pharmacokinetics, and clinical status. Lastly, we also discuss the challenges and future directions for HMT-based drug discovery for cancer therapy.
摘要：
组蛋白甲基转移酶(HMTs)在基因翻译后调控和多种生理过程中发挥重要作用。并与许多人类疾病有关，尤其是癌症。越来越多的证据表明，HMT可以作为癌症治疗的潜在治疗靶点。因此，在过去的十年中,HMTs抑制剂的开发一直受到越来越多的关注.然而,临床疗效不足等缺点，适度的选择性，和获得性抗性的倾向阻碍了常规HMT抑制剂的发展。新的技术和方法对于增强HMT抑制剂的抗癌活性至关重要。在这次审查中,我们首先回顾了几种重要的HMT的结构和生物学功能，如EZH2、G9a、PRMT5和DOT1L。阐述了这些HMTs与癌症的内在联系。接下来,我们主要关注包括双靶点抑制剂在内的HMT调节剂开发的最新进展，从合理设计等角度出发的靶向蛋白质降解剂和共价抑制剂，药效学,药代动力学，和临床状态。最后,我们还讨论了基于HMT的癌症治疗药物发现的挑战和未来方向.
