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

ABSTRACT Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and promising drug target. We previously reported first-generation sEH proteolysis–targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound 8 ) exhibits a half-maximal degradation concentration in the sub-nM range, is stable in vivo , and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.