<i>In Vivo</i> -Active Soluble Epoxide Hydrolase-Targeting PROTACs with Improved Potency and Stability
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 <b>8</b>) exhibits a half-maximal degradation concentration in the sub-nM range, is stable <i>in vivo</i>, 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.
Authors
- Jennifer T. Aguilan (ORCID: https://orcid.org/0000-0002-0221-354X)
- Christophe Morisseau (ORCID: https://orcid.org/0000-0002-5672-6631)
- Kosaku Shinoda (ORCID: https://orcid.org/0000-0002-1928-0749)
- Bruce D. Hammock (ORCID: https://orcid.org/0000-0003-1408-8317)
- Presley Dowker-Key (ORCID: https://orcid.org/0000-0002-1814-004X)
- Seiya Kitamura (ORCID: https://orcid.org/0000-0003-2453-849X)
- Keita Nakane (ORCID: https://orcid.org/0000-0002-2589-1722)
- Ahmed Bettaieb (ORCID: https://orcid.org/0000-0003-2894-9608)
- Simone Sidoli (ORCID: https://orcid.org/0000-0001-9073-6641)
- Emiko Nagai (ORCID: https://orcid.org/0000-0003-4991-7306)
- Gabrielle Benitez (ORCID: https://orcid.org/0000-0002-3564-9462)
Institutions
- Albert Einstein College of Medicine (US)
- UC Davis Comprehensive Cancer Center
- University of Tennessee at Knoxville (US)
- University of California, Davis (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00357
- Citations
- 5
- Primary Topic
- Eicosanoids and Hypertension Pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 1.47
Funders
- American Federation for Aging Research
- Merck
- Albert Einstein Cancer Center
- Relay Therapeutics
- National Institutes of Health
- Albert Einstein College of Medicine, Yeshiva University
- University of California, Davis
- NIH Office of the Director
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- National Institute of Environmental Health Sciences
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine
- Comprehensive Cancer Center, University of California, Davis