5H8B

Crystal structure of CK2 with compound 2

5H8B の概要

• エントリーDOI: 10.2210/pdb5h8b/pdb
• 関連するPDBエントリー: 5H8E 5H8G
• 分子名称: Casein kinase II subunit alpha, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: kinase, inhibitor, ck2, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P68400
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83060.11

構造登録者

Ferguson, A.D. (登録日: 2015-12-23, 公開日: 2016-02-10, 最終更新日: 2023-09-27)

主引用文献

Dowling, J.E.,Alimzhanov, M.,Bao, L.,Chuaqui, C.,Denz, C.R.,Jenkins, E.,Larsen, N.A.,Lyne, P.D.,Pontz, T.,Ye, Q.,Holdgate, G.A.,Snow, L.,O'Connell, N.,Ferguson, A.D.
Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo.
Acs Med.Chem.Lett., 7:300-305, 2016

PubMed Abstract: The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and β-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts.

PubMed: 26985319
DOI: 10.1021/acsmedchemlett.5b00452

実験手法

X-RAY DIFFRACTION (2.55 Å)