2. Academic Validation
  3. Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase

Structure-Based Design of PROTACS for the Degradation of Soluble Epoxide Hydrolase

  • J Med Chem. 2025 Jul 10;68(13):13728-13749. doi: 10.1021/acs.jmedchem.5c00552.
Julia Schönfeld 1,  Steffen Brunst 1 2,  Ludmila Ciomirtan 3,  Lena Willmer 4 5,  Michel A Chromik 6,  Adarsh Kumar 1,  Timo Froemel 7,  Nick Liebisch 1,  Arne Hackspacher 1,  Johanna H M Ehrler 1,  Lukas Wintermeier 3,  Christina Hesse 4 5,  Jan Fiedler 4,  Jan Heering 2,  Hinrich Freitag 5 8,  Patrick Zardo 9,  Hans-Gerd Fieguth 10,  Astrid Brüggerhoff 1,  Josefine Jakob 11 12,  Björn Häupl 11 12 13 14,  Lilia Weizel 1,  Astrid Kaiser 1,  Manfred Schubert-Zsilavecz 1,  Thomas Oellerich 11 12 13 14 15,  Ingrid Fleming 7,  Nils H Schebb 6,  Robert Fürst 16,  Aimo Kannt 2 17,  Stefan Knapp 1 18,  Ewgenij Proschak 1 2,  Kerstin Hiesinger 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University, 60438 Frankfurt am Main, Germany.
  • 2 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany.
  • 3 Institute of Pharmaceutical Biology, Goethe University, 60438 Frankfurt am Main, Germany.
  • 4 Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Member of Fraunhofer Cluster Immune Mediated Diseases (CIMD), 60596 Frankfurt am Main, Germany.
  • 5 Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.
  • 6 Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, 42119 Wuppertal, Germany.
  • 7 Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany.
  • 8 Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany.
  • 9 Department of Cardiothoracic Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.
  • 10 KRH Clinics Hannover, 30459 Hannover, Germany.
  • 11 Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany.
  • 12 Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany.
  • 13 German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Germany, 60590 Frankfurt am Main, Germany.
  • 14 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 15 University Cancer Center (UCT), 60590 Frankfurt am Main, Germany.
  • 16 Pharmaceutical Biology, Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • 17 Institute for Clinical Pharmacology, Goethe University, 60596 Frankfurt am Main, Germany.
  • 18 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, 60438 Frankfurt am Main, Germany.
PMID: 40532036 DOI: 10.1021/acs.jmedchem.5c00552
Abstract

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 23 was identified in primary human and murine cells, highlighting the potential of using 23 in disease-relevant cell and tissue models.

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