2. Academic Validation
  3. Discovery of the sEH Inhibitor Epoxykynin as a Potent Kynurenine Pathway Modulator

Discovery of the sEH Inhibitor Epoxykynin as a Potent Kynurenine Pathway Modulator

  • J Med Chem. 2024 Mar 12. doi: 10.1021/acs.jmedchem.3c02245.
Lara Dötsch 1 2,  Caitlin Davies 1,  Elisabeth Hennes 1,  Julia Schönfeld 3,  Adarsh Kumar 3 4,  Celine Da Cruz Lopes Guita 1,  Johanna H M Ehrler 3,  Kerstin Hiesinger 3,  Sasikala Thavam 1,  Petra Janning 1,  Sonja Sievers 5,  Stefan Knapp 3 4,  Ewgenij Proschak 3,  Slava Ziegler 1,  Herbert Waldmann 1 2
Affiliations

Affiliations

  • 1 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund 44227, Germany.
  • 2 Department of Chemical Biology, Technical University of Dortmund, Otto-Hahn-Strasse 6, Dortmund 44227, Germany.
  • 3 Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue-Strasse 9, Frankfurt 60438, Germany.
  • 4 Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strasse 15, Frankfurt 60438, Germany.
  • 5 Compound Management and Screening Center (COMAS), Otto-Hahn-Strasse 15, Dortmund 44227, Germany.
PMID: 38470246 DOI: 10.1021/acs.jmedchem.3c02245
Abstract

Disease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes of action (MMOA). Herein, we report the identification and characterization of epoxykynin, a potent inhibitor of the soluble Epoxide Hydrolase (sEH). Epoxykynin was discovered by means of a cellular assay monitoring modulation of kynurenine (Kyn) levels in BxPC-3 cells upon stimulation with the cytokine interferon-γ (IFN-γ) and subsequent target identification employing affinity-based chemical proteomics. Increased Kyn levels are associated with immune suppression in the tumor microenvironment and, thus, the Kyn pathway and its key player indoleamine 2,3-dioxygenase 1 (IDO1) are appealing targets in immuno-oncology. However, targeting IDO1 directly has led to limited success in clinical investigations, demonstrating that alternative approaches to reduce Kyn levels are in high demand. We uncover a cross-talk between sEH and the Kyn pathway that may provide new opportunities to revert cancer-induced immune tolerance.

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