Development of Bifunctional Degraders for Targeted Proteolysis of Histone Deacetylases

Abstract

In recent years, the development of PROteolysis-TArgeting Chimeras (PROTACs) targeting Histone deacetylase (HDAC) has attracted growing attention as a strategy for achieving more precise epigenetic modulation beyond conventional inhibition by small molecules. Many HDAC-targeting PROTACs have been reported, primarily focusing on class I and II HDACs using well-characterized E3 ligases such as Cereblon (CRBN) or Von Hippel–Lindau (VHL). These molecules have shown promising activity in degrading either multiple HDAC subtypes or specific isoforms, offering advantages such as sustained protein knockdown and a catalytic mechanism of action. However, challenges remain. Many existing HDAC PROTACs lack clear isoform selectivity, raising concerns about potential off-target effects and broad-spectrum HDAC depletion. Furthermore, the limited range of E3 ligases employed in HDAC PROTACs may constrain their effectiveness in certain cellular contexts. In contrast, exploring alternative E3 ligases offers an opportunity to diversify degradation strategies and potentially enhance selectivity and/or efficiency. In this context, efforts to refine degradation selectivity and to explore new E3 ligase recruitment strategies represent promising directions for advancing the field. This thesis comprises three distinct yet related research projects aimed at developing PROTACs for selective degradation of HDACs, with particular focus on isoform or class selectivity and the use of novel E3 ligase complex recruitment strategies.