In Vivo-Active Soluble Epoxide Hydrolase-Targeting PROTACs with Improved Potency and Stability.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Soluble epoxide hydrolase (sEH) is a bifunctional enzyme implicated in fatty acid metabolism and disease.
• First-generation sEH proteolysis-targeting chimeras (PROTACs) demonstrated limited degradation efficacy and stability.
• sEH is a validated drug target for various metabolic and nonmetabolic diseases.

Purpose of the Study:

• To develop novel, next-generation sEH PROTACs with improved potency and stability.
• To evaluate the in vivo efficacy and stability of these advanced sEH PROTACs.
• To provide chemical probes for investigating sEH biological roles and therapeutic potential.

Main Methods:

• Design and synthesis of novel sEH PROTAC molecules.
• Biochemical assays to determine degradation potency (e.g., half-maximal degradation concentration).
• In vivo studies assessing compound stability and target engagement in mouse tissues.

Main Results:

• Next-generation sEH PROTACs exhibit significantly enhanced degradation potency, with compound 8 achieving sub-nanomolar degradation concentrations.
• Compound 8 demonstrates excellent in vivo stability and effectively degrades sEH in mouse liver and brown adipose tissue.
• The developed molecules serve as effective chemical probes for sEH biology.

Conclusions:

• The novel sEH PROTACs represent a significant advancement over first-generation compounds.
• These molecules are potent, stable, and suitable for in vivo applications.
• The findings support the therapeutic potential of sEH modulation in diseases like diabetes and inflammation.