Development of Hydrophobic Tag Based HDAC6 Degrader for Ulcerative Colitis Treatment

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Histone deacetylase 6 (HDAC6) plays a role in inflammatory pathways and is a potential therapeutic target for inflammatory diseases.
• Targeted protein degradation using hydrophobic tagging is a novel strategy for disease modulation.

Purpose of the Study:

• To develop novel hydrophobic tag-based HDAC6 degraders.
• To identify a lead compound for treating ulcerative colitis.

Main Methods:

• Modification of Nexturastat A structure to create new HDAC6 degraders.
• In vitro assessment of compound selectivity and degradation efficiency (e.g., half-degradation concentration).
• In vivo studies using a dextran sulfate sodium (DSS)-induced colitis model.
• Transcriptomic and biochemical analyses to elucidate the mechanism of action.

Main Results:

• Compound 20c selectively degrades HDAC6 in vitro (half-degradation concentration = 1.1 μM) in a ubiquitin-proteasome dependent manner, without affecting other HDAC isoforms.
• In a DSS-induced colitis model, 20c alleviated disease symptoms, reduced colon shortening, and decreased pro-inflammatory cytokines.
• 20c was found to suppress NF-κB signaling via the HDAC6-HSP90-NF-κB axis.

Conclusions:

• Hydrophobic tag-based HDAC6 degraders, exemplified by 20c, are effective in degrading HDAC6.
• Compound 20c demonstrates therapeutic potential for ulcerative colitis by targeting the HDAC6-HSP90-NF-κB pathway.