Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε
| Autor: | Fabian Wesseler, Uwe Knippschild, Dennis Schade, Balbina García-Reyes, Bernd Rathmer, Elena Brunstein, Christian Pichlo, Doris Henne-Bruns, Björn Jansen, Tanja Gehring, Ebru Karasu, Lydia Witt, Ulrich Baumann, Christian Peifer, Johann Leban |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Casein Kinase 1 epsilon Protein Conformation Mutant Binding Competitive 03 medical and health sciences 0302 clinical medicine Adenosine Triphosphate Palmitoylation Cell Line Tumor Drug Discovery Transferase Humans Protein Kinase Inhibitors Cell Proliferation Kinase Chemistry Wnt signaling pathway Ligand (biochemistry) PORCN Wnt Proteins 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Casein Kinase Idelta Drug Design Molecular Medicine Benzimidazoles Casein kinase 1 |
| Zdroj: | Journal of medicinal chemistry. 61(9) |
| ISSN: | 1520-4804 |
| Popis: | 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/e-related pathways. |
| Databáze: | OpenAIRE |
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