Developmentof Ethyl-Hydrazide-Based Selective HistoneDeacetylase 6 (HDAC6) PROTACs

Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors and degraders rely on the potentially genotoxic hydroxamate as a zinc-binding group (ZBG). In this study, we present the development of HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety as an alternative ZBG. This approach avoids the genotoxicity concerns of hydroxamates while maintaining potent HDAC6 degradation. We synthesized a series of CRBN- and VHL-recruiting PROTACs and identified several potent HDAC6 degraders (HDAC6 <i>D</i>_max > 80%). Among these, <b>17c</b> was the most effective, achieving an HDAC6 degradation of 91% and a DC₅₀ value of 14 nM. Further characterization proved that <b>17c</b> acts via the ubiquitin–proteasome system and chemoproteomics confirmed selective HDAC6 degradation over other HDAC isoforms.