Epigenetic therapy meets targeted protein degradation: HDAC-PROTACs in cancer treatment

Epigenetic therapy and targeted protein degradation have converged in the development of histone deacetylases (HDACs)-targeting proteolysis-targeting chimeras (PROTACs), offering a novel approach to cancer treatment. Unlike traditional HDAC inhibitors, HDAC-PROTACs facilitate selective degradation of HDACs via the ubiquitin-proteasome system, effectively eliminating both enzymatic and scaffolding functions. These bifunctional molecules recruit HDACs to E3 ligases, triggering ubiquitination and subsequent proteasomal degradation. PROTACs demonstrate catalytic activity, requiring lower dosages while sustaining prolonged effects compared to inhibitors. Advances in PROTAC chemistry have led to the development of selective degraders targeting distinct HDAC classes. Class I HDAC-targeting PROTACs, such as PROTAC 1 and PROTAC 2, induce robust degradation of HDAC1-3 with nanomolar DC50 values, showing promising anti-cancer activity. Similarly, class IIa and IIb HDAC PROTACs, including selective HDAC4 and HDAC6 degraders, exhibit potent anti-proliferative effects in leukemia, lymphoma, and multiple myeloma models. Despite these advancements, challenges persist in optimizing selectivity, linker design, and bioavailability while mitigating off-target effects. Future strategies include enhancing tumor-specific delivery, refining ligand-E3 ligase compatibility, and integrating combination therapies to overcome resistance. This review explores the mechanistic insights, therapeutic potential, and challenges associated with HDAC-targeting PROTACs, highlighting their promising role in precision oncology.