Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies
Ziqian Huang, Ling Li, Binbin Cheng, Deping Li
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. This review summarizes the recent progress in the development of histone deacetylase 6 (HDAC6) modulators encompassing isoform-selective inhibitors, dual-target inhibitors, and targeted protein degradation (TPD) technology, with deep insights into the potential challenges and corresponding remedies. • Recent progress on histone deacetylase 6 (HDAC6)-based drug discovery was reviewed. • HDAC6 modulators (selective inhibitors, dual inhibitors, targeted protein degradation (TPD) technology) were overviewed. • Prospects and future directions of HDAC6-targeting cancer therapy were provided.