State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, PR China.
Eur J Med Chem. 2023 Nov 15;260:115746. doi: 10.1016/j.ejmech.2023.115746. Epub 2023 Aug 19.
Inducing protein degradation by proteolysis targeting chimera (PROTAC) has provided great opportunities for scientific research and industrial applications. Histone deacetylase (HDAC)-PROTAC has been widely developed since the first report of its ability to induce the degradation of SIRT2 in 2017. To date, ten of the eighteen HDACs (HDACs 1-8, HDAC10, and SIRT2) have been successfully targeted and degraded by HDAC-PROTACs. HDAC-PROTACs surpass traditional HDAC inhibitors in many aspects, such as higher selectivity, more potent antiproliferative activity, and the ability to disrupt the enzyme-independent functions of a multifunctional protein and overcome drug resistance. Rationally designing HDAC-PROTACs is a main challenge in development because slight variations in chemical structure can lead to drastic effects on the efficiency and selectivity of the degradation. In the future, HDAC-PROTACs can potentially be involved in clinical research with the support of the increased amount of in vivo data, pharmacokinetic evaluation, and pharmacological studies.
通过蛋白水解靶向嵌合体（PROTAC）诱导蛋白质降解为科学研究和工业应用提供了巨大的机会。自 2017 年首次报道其能够诱导 SIRT2 降解以来，组蛋白去乙酰化酶（HDAC）-PROTAC 得到了广泛的发展。迄今为止，已有十八个 HDAC 中的十个（HDACs 1-8、HDAC10 和 SIRT2）被 HDAC-PROTAC 成功靶向和降解。HDAC-PROTAC 在许多方面超越了传统的 HDAC 抑制剂，例如更高的选择性、更强的抗增殖活性、以及破坏多功能蛋白的酶非依赖性功能和克服耐药性的能力。合理设计 HDAC-PROTAC 是开发的主要挑战，因为化学结构的细微变化可能会对降解的效率和选择性产生巨大影响。在未来，随着更多的体内数据、药代动力学评估和药理学研究的支持，HDAC-PROTAC 可能会涉及临床研究。
