2. Academic Validation
  3. Combined Proteomic and In Silico Target Identification Reveal a Role for 5-Lipoxygenase in Developmental Signaling Pathways

Combined Proteomic and In Silico Target Identification Reveal a Role for 5-Lipoxygenase in Developmental Signaling Pathways

  • Cell Chem Biol. 2018 Sep 20;25(9):1095-1106.e23. doi: 10.1016/j.chembiol.2018.05.016.
Silke Brand 1,  Sayantani Roy 2,  Peter Schröder 1,  Bernd Rathmer 3,  Jessica Roos 4,  Shobhna Kapoor 2,  Sumersing Patil 2,  Claudia Pommerenke 5,  Thorsten Maier 6,  Petra Janning 2,  Sonja Eberth 5,  Dieter Steinhilber 4,  Dennis Schade 3,  Gisbert Schneider 7,  Kamal Kumar 2,  Slava Ziegler 2,  Herbert Waldmann 8
Affiliations

Affiliations

  • 1 Max Planck Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, Dortmund 44227, Germany; Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, Dortmund 44227, Germany.
  • 2 Max Planck Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, Dortmund 44227, Germany.
  • 3 Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, Dortmund 44227, Germany.
  • 4 Goethe Universität, Institut für Pharmazeutische Chemie, Max-von-Laue-Strasse 9, Frankfurt am Main 60438, Germany.
  • 5 Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Inhoffenstraße 7B, Braunschweig 38124, Germany.
  • 6 Department for Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, Frankfurt 60590, Germany; Aarhus University, Department of Biomedicine, Bartholins Allé 6, Aarhus C 8000, Denmark.
  • 7 ETH Zürich, Institut für Pharmazeutische Wissenschaften, Vladimir-Prelog-Weg 1-5/10, Zürich CH-8093, Switzerland.
  • 8 Max Planck Institut für Molekulare Physiologie, Otto-Hahn-Strasse 11, Dortmund 44227, Germany; Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, Dortmund 44227, Germany. Electronic address: herbert.waldmann@mpi-dortmund.mpg.de.
PMID: 30251630 DOI: 10.1016/j.chembiol.2018.05.016
Abstract

Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method may provide efficient guidance for target candidate selection and prioritization for experimental in-depth evaluation. We identify 5-lipoxygenase (5-LO) as the target of the Wnt pathway inhibitor Lipoxygenin. Lipoxygenin is a non-redox 5-LO inhibitor, modulates the β-catenin-5-LO complex and induces reduction of both β-catenin and 5-LO levels in the nucleus. Lipoxygenin and the structurally unrelated 5-LO inhibitor CJ-13,610 promote cardiac differentiation of human induced pluripotent stem cells and inhibit Hedgehog, TGF-β, BMP, and Activin A signaling, suggesting an unexpected and yet unknown role of 5-LO in these developmental pathways.

Keywords

Wnt pathway; cell-based screening; lipoxygenase; target identification; target prediction.

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