Histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-l-lysine side chains in histones and non-histones, which are key to epigenetic regulation in humans. Targeting HDACs has emerged as a promising strategy for treating various types of cancer, including myeloma and hematologic malignancies. At present, numerous small molecule inhibitors targeting HDACs are actively being investigated in clinical trials. Despite their potential efficacy in cancer treatment, HDAC inhibitors suffer from multi-directional selectivity and preclinical resistance issues. Hence, developing novel inhibitors based on cutting-edge medicinal chemistry techniques is essential to overcome these limitations and improve clinical outcomes. This manuscript presents an extensive overview of the properties and biological functions of HDACs in cancer, provides an overview of the current state of development and limitations of clinical HDAC inhibitors, and analyzes a range of innovative medicinal chemistry techniques that are applied. These techniques include selective inhibitors, dual-target inhibitors, proteolysis targeting chimeras, and protein-protein interaction inhibitors.

组蛋白脱乙酰酶 (HDAC) 催化组蛋白和非组蛋白中乙酰基-L-赖氨酸侧链的水解，这是人类表观遗传调控的关键。靶向 HDAC 已成为治疗各种类型癌症（包括骨髓瘤和血液恶性肿瘤）的一种有前途的策略。目前，多种针对HDAC的小分子抑制剂正在临床试验中积极研究。尽管 HDAC 抑制剂在癌症治疗中具有潜在功效，但仍面临多向选择性和临床前耐药性问题。因此，开发基于尖端药物化学技术的新型抑制剂对于克服这些限制并改善临床结果至关重要。本手稿广泛概述了 HDAC 在癌症中的特性和生物学功能，概述了临床 HDAC 抑制剂的发展现状和局限性，并分析了一系列所应用的创新药物化学技术。这些技术包括选择性抑制剂、双靶点抑制剂、靶向嵌合体的蛋白水解以及蛋白质-蛋白质相互作用抑制剂。