Abstract：
Histone deacetylase 6 (HDAC6) plays a crucial role in the initiation and progression of various cancers, as its overexpression is linked to tumor growth, invasion, migration, survival, apoptosis, and angiogenesis. Therefore, HDAC6 has emerged as an attractive target for anticancer drug discovery in the past decade. However, the development of conventional HDAC6 inhibitors has been hampered by their limited clinical efficacy, acquired resistance, and inability to inhibit non-enzymatic functions of HDAC6. To overcome these challenges, new strategies, such as dual-acting inhibitors, targeted protein degradation (TPD) technologies (including PROTACs, HyT), are essential to enhance the anticancer activity of HDAC6 inhibitors. In this review, we focus on the recent advances in the design and development of HDAC6 modulators, including isoform-selective HDAC6 inhibitors, HDAC6-based dual-target inhibitors, and targeted protein degraders (PROTACs, HyT), from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and clinical status. Finally, we discuss the challenges and future directions for HDAC6-based drug discovery for cancer therapy.
摘要：
组蛋白去乙酰化酶6(HDAC6)在各种癌症的发生和发展中起着至关重要的作用。因为它的过度表达与肿瘤生长有关，入侵,迁移,生存,凋亡，和血管生成。因此,在过去的十年中，HDAC6已成为抗癌药物发现的有吸引力的靶标。然而,常规HDAC6抑制剂的开发因其有限的临床疗效而受到阻碍，获得性抵抗力，并且不能抑制HDAC6的非酶功能。为了克服这些挑战，新战略,如双重作用抑制剂，靶向蛋白质降解(TPD)技术(包括PROTACs，HyT),对增强HDAC6抑制剂的抗癌活性至关重要。在这次审查中,我们专注于HDAC6调制器的设计和开发的最新进展，包括同工型选择性HDAC6抑制剂，基于HDAC6的双靶点抑制剂，和靶向蛋白质降解剂(PROTACs，HyT),从合理设计的角度来看，药效学,药代动力学，和临床状态。最后,我们讨论了基于HDAC6的癌症治疗药物发现的挑战和未来方向.
