Small molecule degraders of soluble epoxide hydrolase as novel therapeutics for diabetes

Although first-generation soluble epoxide hydrolase (sEH) inhibitor entered clinical trials more than 10 years ago for the treatment of insulin resistance and diabetes, there are currently still no drugs on market targeting this promising therapeutic target for diabetes. As an alternative approach to such conventional inhibitors, the first-in-class small molecule sEH degraders were recently developed by our group that promote the degradation of sEH within cells with superior cellular efficacy compared to sEH inhibitors. The long-term goal of this application is to show the proof-of-concept that small molecule induced degradation of sEH is a promising pharmacological approach for the treatment of diabetes. The central hypothesis is that small molecule sEH degrader has higher efficacy to reduce hepatic insulin resistance and BAT regression compared to sEH inhibitors. The rationale for this project is that a determination of the preclinical therapeutic efficacy of sEH degraders in animal model of diabetes will offer a strong scientific framework whereby new strategies to diabetes therapy in patients can be developed. The central hypothesis will be tested by pursuing two specific aims: (1) Test the in vivo efficacy of sEH degrader on hepatic insulin resistance, and (2) Compare the effect of sEH degrader vs inhibitor on BAT regression. Under the first aim, high fat diet-induced diabetic mouse model will be used to evaluate the in vivo efficacy of sEH degrader vs sEH inhibitor on insulin resistance of liver. For the second aim, the in vivo effects of sEH degrader on BAT regression will be evaluated in comparison with sEH inhibitor. The research proposed in this application is innovative because it focuses on sEH degrader as a new modality of sEH targeting therapeutics that show high degradation potency with prolonged and superior efficacy. The proposed project is significant because it is expected to provide strong scientific justification for the continued development and future clinical trials of sEH degraders. More in general, our proposed project will show the in vivo efficacy of the first small molecule degraders targeting diabetes, ultimately providing new opportunities for the development of novel therapeutic modality to treat diabetes.