PROTAC‐Based HDAC Degradation: A Paradigm Shift in Targeted Epigenetic Therapies

Proteolysis-targeting chimeras (PROTACs) have emerged as an excellent strategy for targeted protein degradation by the ubiquitin-proteasome system. Traditional inhibitors suppress the enzymatic activity, but the PROTACs utilize the method of total degradation of protein, promising prolonged and target-specific therapeutic efficacy. Histone deacetylases (HDACs) are epigenetic regulators, implicated in most cancers, neurodegeneration, and other inflammatory diseases. Therefore, HDAC-PROTAC development provides a unique approach to overcome the limitations of conventional HDAC inhibitors, including off-target effects, short duration of action, and resistance mechanisms. Recent advancements in HDAC-PROTACs lead to the design of selective degraders for specific isoforms of HDACs, including HDAC3, HDAC4, HDAC6, and HDAC8, representing superior efficacy in preclinical studies. This review highlights the progress of HDAC-targeting PROTACs, focusing on structural optimization, selectivity enhancements, and therapeutic applications with their degradation potential. However, various challenges include poor pharmacokinetics and bioavailability, and limited in vivo validation for further safety, efficacy analysis. Further research and optimization efforts will be pivotal in translating HDAC-PROTACs into clinically viable therapies for cancer and other epigenetic disorders.