Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
China Meheco Topfond Pharmaceutical Co., Ltd., Zhumadian, 463000, PR China.
J Med Chem. 2021 Feb 11;64(3):1362-1391. doi: 10.1021/acs.jmedchem.0c01782. Epub 2021 Feb 1.
Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC6 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC6 inhibitors have been effectively used to treat cancers, neurodegenerative diseases, and autoimmune disorders without exerting significant toxic effects. Progress has been made in defining the crystal structures of HDAC6 catalytic domains which has influenced the structure-based drug design of HDAC6 inhibitors. This review summarizes recent literature on HDAC6 inhibitors with particular reference to structural specificity and functional diversity. It may provide up-to-date guidance for the development of HDAC6 inhibitors and perspectives for optimization of therapeutic applications.
组蛋白去乙酰化酶（HDACs）通过催化组蛋白去乙酰化作用对于维持内稳态至关重要。HDACs 的异常表达与多种人类疾病有关。尽管 HDAC 抑制剂在临床实践中被用作有效的化疗药物，但由于其弱的同工型选择性引起的相关副作用，其应用仍然有限。HDAC6 具有独特的结构和细胞定位以及不同的底物，并表现出比其他同工型更广泛的生物学功能。HDAC6 抑制剂已被有效地用于治疗癌症、神经退行性疾病和自身免疫性疾病，而没有产生显著的毒性作用。在确定 HDAC6 催化结构域的晶体结构方面取得了进展，这影响了 HDAC6 抑制剂的基于结构的药物设计。本综述总结了最近关于 HDAC6 抑制剂的文献，特别参考了结构特异性和功能多样性。它可能为 HDAC6 抑制剂的开发提供最新的指导，并为优化治疗应用提供新的视角。
