Design, Synthesis, and Anti-inflammatory Activity Evaluation for Hydrazide-Based HDAC6 Targeted Protein Degraders.

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Immunology

Background:

• Histone deacetylase 6 (HDAC6) is a key regulator of inflammatory signaling pathways.
• Targeting HDAC6 offers a promising therapeutic strategy for inflammatory conditions.
• Previous work established hydrazide-based HDAC6 inhibitors with good pharmacokinetics.

Purpose of the Study:

• To design and synthesize novel hydrazide-based HDAC6 degraders.
• To evaluate the efficacy of these degraders in inhibiting inflammatory signaling.
• To assess the therapeutic potential of HDAC6 degraders in a preclinical model of colitis.

Main Methods:

• Rational design and synthesis of hydrazide-based HDAC6 degraders.
• Biochemical assays to determine HDAC6 degradation potency (DC50) and selectivity.
• Inhibition assays for NLRP3 inflammasome and NF-κB signaling pathways.
• In vivo studies using a DSS-induced mouse colitis model.

Main Results:

• Compound 22f potently and selectively degraded HDAC6 via the ubiquitin-proteasome pathway (DC50 = 13.4 nM).
• 22f inhibited NLRP3 inflammasome assembly/activation and NF-κB signaling.
• 22f treatment significantly reduced disease severity and tissue damage in a mouse colitis model.

Conclusions:

• Hydrazide-based HDAC6 degraders represent a first-in-class approach to simultaneously target HDAC6's catalytic and binding domains.
• Compound 22f demonstrates potent anti-inflammatory effects by inhibiting key signaling pathways.
• HDAC6 PROTAC molecules hold significant therapeutic potential for inflammatory bowel disease.