4KB8

CK1d in complex with 1-{4-[3-(4-FLUOROPHENYL)-1-METHYL-1H-PYRAZOL-4-YL]PYRIDIN-2-YL}-N-METHYLMETHANAMINE ligand

Summary for 4KB8

• Entry DOI: 10.2210/pdb4kb8/pdb
• Related: 4KBA 4KBC 4KBH 4KBK
• Descriptor: Casein kinase I isoform delta, 1-{4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridin-2-yl}-N-methylmethanamine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: ser/thr kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48730
• Total number of polymer chains: 4
• Total formula weight: 156034.70

Authors

Liu, S. (deposition date: 2013-04-23, release date: 2013-09-18, Last modification date: 2024-02-28)

Primary citation

Mente, S.,Arnold, E.,Butler, T.,Chakrapani, S.,Chandrasekaran, R.,Cherry, K.,Dirico, K.,Doran, A.,Fisher, K.,Galatsis, P.,Green, M.,Hayward, M.,Humphrey, J.,Knafels, J.,Li, J.,Liu, S.,Marconi, M.,McDonald, S.,Ohren, J.,Paradis, V.,Sneed, B.,Walton, K.,Wager, T.
Ligand-protein interactions of selective casein kinase 1 delta inhibitors.
J.Med.Chem., 56:6819-6828, 2013

PubMed Abstract: Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1ε-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1δ isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.

PubMed: 23919824
DOI: 10.1021/jm4006324

Experimental method

X-RAY DIFFRACTION (1.95 Å)