2. Academic Validation
  3. Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε

Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε

  • J Med Chem. 2018 May 10;61(9):4087-4102. doi: 10.1021/acs.jmedchem.8b00095.
Balbina García-Reyes 1,  Lydia Witt 2,  Björn Jansen 2,  Ebru Karasu 1,  Tanja Gehring 1,  Johann Leban 3,  Doris Henne-Bruns 1,  Christian Pichlo 4,  Elena Brunstein 4,  Ulrich Baumann 4,  Fabian Wesseler 5,  Bernd Rathmer 5,  Dennis Schade 5 6,  Christian Peifer 2,  Uwe Knippschild 1
Affiliations

Affiliations

  • 1 Department of General and Visceral Surgery , Ulm University Hospital , Albert-Einstein-Allee 23 , D-89081 Ulm , Germany.
  • 2 Institute of Pharmacy , Christian-Albrechts-University of Kiel , Gutenbergstraße 76 , D-24116 Kiel , Germany.
  • 3 Oncotyrol GmbH , Karl-Kapferer-Straße 5 , 6020 Innsbruck , Austria.
  • 4 Department for Chemistry , University of Cologne , Zülpicher Str. 47B , D-50674 Cologne , Germany.
  • 5 Department of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn-Str. 6 , D-44227 Dortmund , Germany.
  • 6 Institute of Pharmacy , Ernst-Moritz-Arndt-University of Greifswald , Felix-Hausdorff-Str. 1 , D-17489 Greifswald , Germany.
PMID: 29630366 DOI: 10.1021/acs.jmedchem.8b00095
Abstract

Inhibitors of Wnt production (IWPs) are known antagonists of the Wnt pathway, targeting the membrane-bound O-acyltransferase Porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation. Since IWPs show structural similarities to benzimidazole-based CK1 inhibitors, we hypothesized that IWPs could also inhibit CK1 isoforms. Molecular modeling revealed a plausible binding mode of IWP-2 in the ATP binding pocket of CK1δ which was confirmed by X-ray analysis. In vitro kinase assays demonstrated IWPs to be ATP-competitive inhibitors of wtCK1δ. IWPs also strongly inhibited the gatekeeper mutant M82FCK1δ. When profiled in a panel of 320 kinases, IWP-2 specifically inhibited CK1δ. IWP-2 and IWP-4 also inhibited the viability of various Cancer cell lines. By a medicinal chemistry approach, we developed improved IWP-derived CK1 inhibitors. Our results suggest that the effects of IWPs are not limited to Porcn, but also might influence CK1δ/ε-related pathways.

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