4KBA

CK1d in complex with 9-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine inhibitor

4KBA の概要

• エントリーDOI: 10.2210/pdb4kba/pdb
• 関連するPDBエントリー: 4KB8 4KBC 4KBH 4KBK
• 分子名称: Casein kinase I isoform delta, 9-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: ser/thr kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P48730
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 156310.87

構造登録者

Liu, S. (登録日: 2013-04-23, 公開日: 2013-09-18, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.98 Å)