Unlocking the therapeutic potential of HDAC8-degrading PROTACs: progress, challenges, and future directions

Abstract

Histone deacetylase 8 (HDAC8) is a class I enzyme associated with various diseases, including cancer and neurological disorders. Although small-molecule HDAC inhibitors have been developed, their lack of selectivity often leads to off-target effects and toxicities. Alternatively, targeting specific HDAC isoforms for their degradation represents a more precise therapeutic strategy. This review focuses on the design and development of proteolysis-targeting chimeras (PROTACs) that selectively degrade HDAC8. We explore how existing selective HDAC8 inhibitors can be leveraged as warheads in PROTACs to effectively eliminate the enzyme. Recent studies have successfully designed HDAC8-selective PROTACs by linking HDAC8 inhibitors to E3 ubiquitin ligase recruiters such as VHL and CRBN. These PROTACs have demonstrated high potency in degrading HDAC8 in various cancer cell lines with single-digit nanomolar DC₅₀ values, showing superior anti-proliferative effects compared to their parent inhibitors. Therefore, apart from these handful of reports, more research related to HDAC8-PROTAC should provide a better therapeutic development technology for HDAC8-associated disorders while avoiding any therapy-related adversities and complications.