6F26

Crystal structure of human Casein Kinase I delta in complex with compound 31b

Summary for 6F26

• Entry DOI: 10.2210/pdb6f26/pdb
• Descriptor: Casein kinase I isoform delta, SULFATE ION, (9~{S},10~{S},11~{R})-~{N}-[4-[3-(4-fluorophenyl)-5-propan-2-yl-1,2-oxazol-4-yl]pyridin-2-yl]-4-(4-methoxyphenyl)-10,11-bis(oxidanyl)-1,7-diazatricyclo[7.3.0.0^{3,7}]dodeca-3,5-diene-6-carboxamide, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, complex, ck1, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 75828.32

Authors

Pichlo, C.,Brunstein, E.,Baumann, U. (deposition date: 2017-11-23, release date: 2019-03-13, Last modification date: 2024-01-17)

Primary citation

Luxenburger, A.,Schmidt, D.,Ianes, C.,Pichlo, C.,Kruger, M.,von Drathen, T.,Brunstein, E.,Gainsford, G.J.,Baumann, U.,Knippschild, U.,Peifer, C.
Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds.
Molecules, 24:-, 2019

PubMed Abstract: In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral "ribose-like" pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.

PubMed: 30832206
DOI: 10.3390/molecules24050873

Experimental method

X-RAY DIFFRACTION (1.83 Å)