In vivo -Active Soluble Epoxide Hydrolase-targeting PROTACs with Improved Potency and Stability

Area of Science:

• Biochemistry
• Pharmacology

Background:

• Soluble epoxide hydrolase (sEH) is a key enzyme in fatty acid metabolism and a potential drug target.
• Previous sEH proteolysis-targeting chimeras (PROTACs) had limited degradation potency and stability.

Purpose of the Study:

• To develop next-generation sEH PROTACs with enhanced stability and degradation potency.
• To provide improved chemical probes for studying sEH biology.

Main Methods:

• Design and synthesis of novel sEH PROTAC molecules.
• Evaluation of degradation potency (e.g., half-maximal degradation concentration).
• Assessment of in vivo stability and efficacy in mouse tissues.

Main Results:

• The most potent molecule (compound 8) achieved sub-nanomolar degradation concentrations.
• Compound 8 demonstrated excellent in vivo stability.
• Effective degradation of sEH was observed in mouse liver and brown adipose tissue.

Conclusions:

• Next-generation sEH PROTACs exhibit significantly improved potency and stability.
• These molecules serve as valuable tools for investigating sEH's role in health and disease.
• The developed PROTACs hold therapeutic potential for metabolic and inflammatory diseases.