Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase
The bifunctional soluble epoxide hydrolase (sEH) represents a promising target for inflammation-related diseases. Although potent inhibitors targeting each domain are available, sEH-PROTACs offer the unique ability to simultaneously block both enzymatic functions, mimicking the sEH knockout phenotype, which has been associated with reducing inflammation, including neuroinflammation, and delaying the progression of Alzheimer's disease. Herein, we report the structure-based development of a potent sEH-PROTAC as a useful pharmacological tool. In order to facilitate a rapid testing of the PROTACs, a cell-based sEH degradation assay was developed utilizing HiBiT technology. We designed and synthesized 24 PROTACs. Furthermore, cocrystallization of sEH with two selected PROTACs allowed us to explore the binding mode and rationalize the most optimal linker length. After comprehensive biological and physicochemical characterization of this series, the most optimal PROTAC <b>23</b> was identified in primary human and murine cells, highlighting the potential of using <b>23</b> in disease-relevant cell and tissue models.
Authors
- Robert Fürst (ORCID: https://orcid.org/0000-0002-9926-7578)
- Ewgenij Proschak (ORCID: https://orcid.org/0000-0003-1961-1859)
- Patrick Zardo (ORCID: https://orcid.org/0000-0003-4003-4945)
- Kerstin Hiesinger (ORCID: https://orcid.org/0000-0001-5458-816X)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Thomas Oellerich (ORCID: https://orcid.org/0000-0001-6570-6125)
- Jan Heering (ORCID: https://orcid.org/0000-0002-4922-1993)
- Steffen Brunst
- Astrid Brüggerhoff
- Manfred Schubert‐Zsilavecz
- Astrid Kaiser
- Aimo Kannt (ORCID: https://orcid.org/0000-0002-5197-2286)
- Johanna H. M. Ehrler (ORCID: https://orcid.org/0000-0001-7990-4042)
- Hans‐Gerd Fieguth (ORCID: https://orcid.org/0000-0003-1559-158X)
- Josefine Jakob
- Julia Schönfeld
- Nils Helge Schebb (ORCID: https://orcid.org/0000-0003-1299-6629)
- Adarsh Kumar (ORCID: https://orcid.org/0000-0002-8219-0332)
- Björn Häupl (ORCID: https://orcid.org/0009-0000-9445-9565)
- Timo Froemel
- Lilia Weizel (ORCID: https://orcid.org/0000-0002-0373-2114)
- Hinrich Freitag (ORCID: https://orcid.org/0000-0003-3824-9867)
- Jan Fiedler (ORCID: https://orcid.org/0000-0002-8855-2883)
- Ingrid Fleming (ORCID: https://orcid.org/0000-0003-1881-3635)
- L. Willmer
- Christina Hesse (ORCID: https://orcid.org/0000-0003-2889-7027)
- Ludmila Ciomirtan
- Nick Liebisch
- Lukas Wintermeier
- Michel André Chromik
- Arne Hackspacher
Institutions
- Goethe University Frankfurt (DE)
- Center for Drug Evaluation and Research (US)
- Goethe-Institute United Kingdom (GB)
- University of Wuppertal (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Structural Genomics Consortium (CA)
- Medizinische Hochschule Hannover (DE)
- Kinderkrankenhaus auf der Bult (DE)
- Klinikum Region Hannover (DE)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- Palmetto Hematology Oncology (US)
- Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
- German Center for Lung Research (DE)
- University Hospital Frankfurt (DE)
- Taipei Institute of Pathology (TW)
- Frankfurt Cancer Institute (DE)
- Hannover Re (Germany) (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00552
- Citations
- 7
- Primary Topic
- Eicosanoids and Hypertension Pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 7.78
Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe