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. 2024 Oct 3;15(11):1891-1898.
doi: 10.1021/acsmedchemlett.4c00357. eCollection 2024 Nov 14.

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

Keita Nakane  1 , Christophe Morisseau  2 , Presley D Dowker-Key  3 , Gabrielle Benitez  4 , Jennifer T Aguilan  1 , Emiko Nagai  1 , Simone Sidoli  1 , Bruce D Hammock  2 , Ahmed Bettaieb  3 , Kosaku Shinoda  4   5 , Seiya Kitamura  1
Affiliations

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

Keita Nakane et al. ACS Med Chem Lett. .

Abstract

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and a 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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): C.M. and B.D.H. are inventors on patents related to the use of sEH inhibitors owned by the University of California. S.K., K.N., C.M., and B.D.H. hold a patent application for the compounds described in this paper (Provisional Application No. 63/642,039).

Update of

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