5OKT

Crystal structure of human Casein Kinase I delta in complex with IWP-2

Summary for 5OKT

• Entry DOI: 10.2210/pdb5okt/pdb
• Descriptor: Casein kinase I isoform delta, ~{N}-(6-methyl-1,3-benzothiazol-2-yl)-2-[(4-oxidanylidene-3-phenyl-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)sulfanyl]ethanamide, SULFATE ION, ... (7 entities in total)
• Functional Keywords: ck1d, kinase-inhibitor complex, transferase, kinase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 149849.57

Authors

Pichlo, C.,Brunstein, E.,Baumann, U. (deposition date: 2017-07-25, release date: 2018-04-25, Last modification date: 2024-01-17)

Primary citation

Garcia-Reyes, B.,Witt, L.,Jansen, B.,Karasu, E.,Gehring, T.,Leban, J.,Henne-Bruns, D.,Pichlo, C.,Brunstein, E.,Baumann, U.,Wesseler, F.,Rathmer, B.,Schade, D.,Peifer, C.,Knippschild, U.
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., 61:4087-4102, 2018

PubMed 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 CK1δ. IWPs also strongly inhibited the gatekeeper mutant CK1δ. 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.

PubMed: 29630366
DOI: 10.1021/acs.jmedchem.8b00095

Experimental method

X-RAY DIFFRACTION (2.13 Å)