Development of Ethyl-Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs.

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Epigenetics

Background:

• Histone deacetylases (HDACs) are key epigenetic targets for drug discovery.
• Targeted protein degradation is a promising therapeutic strategy.
• Existing HDAC inhibitors and degraders often use genotoxic hydroxamate zinc-binding groups.

Purpose of the Study:

• To develop novel HDAC6-targeted proteolysis-targeting chimeras (PROTACs).
• To utilize an ethyl hydrazide moiety as a non-genotoxic zinc-binding group (ZBG).
• To achieve potent and selective degradation of HDAC6.

Main Methods:

• Synthesis of CRBN- and VHL-recruiting PROTACs.
• Evaluation of HDAC6 degradation using various assays.
• Characterization of degradation mechanism via ubiquitin-proteasome system.
• Chemoproteomics to assess selectivity across HDAC isoforms.

Main Results:

• Several potent HDAC6 degraders were identified, with degradation exceeding 80%.
• Compound 17c showed maximal HDAC6 degradation of 91% and a DC50 of 14 nM.
• Degradation was confirmed to proceed through the ubiquitin-proteasome system.
• Chemoproteomics confirmed selective degradation of HDAC6 over other HDACs.

Conclusions:

• Ethyl hydrazide serves as an effective and safer alternative ZBG for HDAC degraders.
• Developed PROTACs offer a promising approach for targeted HDAC6 degradation.
• Compound 17c represents a highly effective and selective HDAC6 degrader.