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.

中文翻译：

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组蛋白脱乙酰基酶6抑制剂研究进展综述：结构特异性和功能多样性。

组蛋白脱乙酰基酶（HDACs）通过催化组蛋白脱乙酰基化对维持体内平衡至关重要。HDAC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用作有效的化学治疗剂，但由于弱亚型选择性引起的相关副作用，其应用仍然受到限制。HDAC6显示出独特的结构和细胞定位以及各种底物，并且比其他同工型具有更广泛的生物学功能。HDAC6抑制剂已有效地用于治疗癌症，神经退行性疾病和自身免疫性疾病，而不会产生明显的毒性作用。在定义HDAC6催化域的晶体结构方面已取得进展，该结构已影响HDAC6抑制剂的基于结构的药物设计。这篇综述总结了有关HDAC6抑制剂的最新文献，特别是关于结构特异性和功能多样性的文献。它可以为HDAC6抑制剂的开发提供最新指南，并为优化治疗应用提供前景。