组蛋白去乙酰化酶（HDACs）催化组蛋白和非组蛋白中乙酰化赖氨酸侧链的水解作用，这在人体中是表观遗传调控的关键。针对HDACs的靶向治疗已成为治疗多种癌症（包括骨髓瘤和血液恶性肿瘤）的有希望策略。目前，许多正在临床试验中积极研究HDACs的小分子抑制剂。尽管HDAC抑制剂在癌症治疗中具有潜在疗效，但它们存在多方向选择性和临床前抗药性的问题。因此，基于尖端药物化学技术开发新的抑制剂对于克服这些局限性并改善临床效果至关重要。本文详细概述了HDACs在癌症中的性质和生物学功能，对临床HDAC抑制剂的当前开发状况和局限性进行了概述，并分析了一系列创新的药物化学技术的应用。这些技术包括选择性抑制剂、双靶点抑制剂、蛋白质降解靶向嵌合物和蛋白质-蛋白质相互作用抑制剂。版权所有 © 2023 Elsevier Masson SAS. 保留所有权利。

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.Copyright © 2023 Elsevier Masson SAS. All rights reserved.