The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases, such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving the therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promotes synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.

中文翻译：

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组蛋白脱乙酰酶 6 (HDAC6) 和热休克蛋白 90 (Hsp90) 的双重靶向策略。

设计同时作用于多个信号通路的多靶点药物是药物化学中一个不断发展的领域，特别是用于治疗癌症等复杂疾病。组蛋白去乙酰化酶 6 (HDAC6) 是一种既定的参与肿瘤细胞转化的抗癌药物靶点。作为许多生物过程相互作用的表观遗传酶，HDAC6 已成为旨在提高抗癌药物治疗效果的多药理学研究的有吸引力的目标。例如，分子伴侣热休克蛋白 90 (Hsp90) 是 HDAC6 去乙酰化的底物，多项证据表明同时抑制 HDAC6 和 Hsp90 可促进对不同癌细胞系的协同抗肿瘤作用，强调开发具有多靶点活性的单个分子的潜在好处。本综述将总结 HDAC6 和 Hsp90 之间复杂的相互作用，为该领域的多靶点药物设计和发现方法提供有用的提示。为此，HDAC6 和 Hsp90 复合物的晶体结构将根据讨论结合袋特征和药效团要求进行广泛审查，并为双重抑制剂的设计提供有用的指导。迄今为止获得的多靶点抑制剂的少数例子，主要基于嵌合方法，将被总结并放在上下文中。最后，将比较 HDAC6 和 Hsp90 抑制剂的主要特点，