Garcia-Reyes, Balbina, Witt, Lydia, Jansen, Bjoern, Karasu, Ebru, Gehring, Tanja, Leban, Johann, Henne-Bruns, Doris, Pichlo, Christian, Brunstein, Elena, Baumann, Ulrich, Wesseler, Fabian, Rathmer, Bernd, Schade, Dennis ORCID: 0000-0002-5515-1821, Peifer, Christian and Knippschild, Uwe (2018). Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) delta/epsilon. J. Med. Chem., 61 (9). S. 4087 - 4103. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

Inhibitors of Wnt production (IWPs) are known antagonists of the Wnt pathway, targeting the membrane-bound 0-acyltransferase porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation. Since IWPs show structural similarities to benzimidazole-based CKI inhibitors, we hypothesized that IWPs could also inhibit CKI isoforms. Molecular modeling revealed a plausible binding mode of IWP-2 in the ATP binding pocket of CK1S which was confirmed by X-ray analysis. In vitro kinase assays demonstrated IWPs to be ATP-competitive inhibitors of 'CK1S. IWPs also strongly inhibited the gatekeeper mutant (M82F)CK1 delta. When profiled in a panel of 320 kinases, IWP-2 specifically inhibited CK1S. 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 CK1o/e-related pathways.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Garcia-Reyes, BalbinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karasu, EbruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gehring, TanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leban, JohannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henne-Bruns, DorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichlo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunstein, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wesseler, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rathmer, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schade, DennisUNSPECIFIEDorcid.org/0000-0002-5515-1821UNSPECIFIED
Peifer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knippschild, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-186509
DOI: 10.1021/acs.jmedchem.8b00095
Journal or Publication Title: J. Med. Chem.
Volume: 61
Number: 9
Page Range: S. 4087 - 4103
Date: 2018
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EMBRYONIC STEM-CELLS; POTENT INHIBITORS; IN-VITRO; MOLECULAR-CLONING; PROTEIN; CK1-DELTA; ISOFORMS; EXPRESSION; EPSILON; CANCERMultiple languages
Chemistry, MedicinalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18650

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