Abstract：
Histone Deacetylase 6 (HDAC6) is an essential regulator of histone acetylation processes, exerting influence on a multitude of cellular functions such as cell motility, endocytosis, autophagy, apoptosis, and protein trafficking through its deacetylation activity. The significant implications of HDAC6 in diseases such as cancer, neurodegenerative disorders, and immune disorders have motivated extensive investigation into the development of specific inhibitors targeting this enzyme for therapeutic purposes. Single targeting drugs carry the risk of inducing drug resistance, thus prompting exploration of dual targeting therapy which offers the potential to impact multiple signaling pathways simultaneously, thereby lowering the likelihood of resistance development. While pharmacological studies have exhibited promise in combined therapy involving HDAC6, challenges related to potential drug interactions exist. In response to these challenges, researchers are investigating HDAC6 hybrid molecules which enable the concomitant targeting of HDAC6 and other key proteins, thus enhancing treatment efficacy while mitigating side effects and reducing the risk of resistance compared to traditional combination therapies. The published design strategies for dual targeting inhibitors of HDAC6 are summarized and discussed in this review. This will provide some valuable insights into more novel HDAC6 dual targeting inhibitors to meet the urgent need for innovative therapies in oncology and other related fields.
摘要：
组蛋白去乙酰化酶6（HDAC6）是组蛋白乙酰化过程的重要调节因子，影响多种细胞功能，如细胞运动性，内吞作用,自噬,凋亡，通过其脱乙酰活性进行蛋白质运输。HDAC6在癌症等疾病中的重要意义，神经退行性疾病，和免疫疾病已经激发了对针对该酶用于治疗目的的特异性抑制剂的开发的广泛研究。单一靶向药物存在诱导耐药的风险,从而促进了双重靶向治疗的探索，它提供了同时影响多个信号通路的潜力，从而降低抗性发展的可能性。虽然药理学研究在涉及HDAC6的联合治疗中显示出希望,但存在与潜在药物相互作用相关的挑战。为了应对这些挑战,研究人员正在研究HDAC6杂合分子，这些杂合分子能够同时靶向HDAC6和其他关键蛋白，因此，与传统的联合疗法相比，提高了治疗效果，同时减轻了副作用并降低了抵抗的风险。本文总结并讨论了已发表的HDAC6双靶向抑制剂的设计策略。这将为更多新型HDAC6双靶向抑制剂提供一些有价值的见解，以满足肿瘤学和其他相关领域对创新疗法的迫切需求。
