6RFE

Human protein kinase CK2 alpha in complex with 2-cyano-2-propenamide compound 4

6RFE の概要

• エントリーDOI: 10.2210/pdb6rfe/pdb
• 関連するPDBエントリー: 6RB1 6RCB 6RCM
• 分子名称: Casein kinase II subunit alpha, 1,2-ETHANEDIOL, (~{E})-~{N}-(5-bromanyl-1,3,4-thiadiazol-2-yl)-2-cyano-3-(3-methoxy-4-oxidanyl-phenyl)prop-2-enamide, ... (5 entities in total)
• 機能のキーワード: kinase domain, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40947.35

構造登録者

Dalle Vedove, A.,Zanforlin, E.,Ribaudo, G.,Zagotto, G.,Battistutta, R.,Lolli, G. (登録日: 2019-04-13, 公開日: 2020-04-08, 最終更新日: 2024-01-24)

主引用文献

Dalle Vedove, A.,Zonta, F.,Zanforlin, E.,Demitri, N.,Ribaudo, G.,Cazzanelli, G.,Ongaro, A.,Sarno, S.,Zagotto, G.,Battistutta, R.,Ruzzene, M.,Lolli, G.
A novel class of selective CK2 inhibitors targeting its open hinge conformation.
Eur.J.Med.Chem., 195:112267-112267, 2020

PubMed Abstract: Protein kinase CK2 sustains cancer growth, especially in hematological malignancies. Its inhibitor SRPIN803, based on a 6-methylene-5-imino-1,3,4-thiadiazolopyrimidin-7-one scaffold, showed notable specificity. Our synthesis of the initially proposed SRPIN803 resulted in its constitutional isomer SRPIN803-revised, where the 2-cyano-2-propenamide group does not cyclise and fuse to the thiadiazole ring. Its crystallographic structure in complex with CK2α identifies the structural determinants of the reported specificity. SRPIN803-revised explores the CK2 open hinge conformation, extremely rare among kinases, also interacting with side chains from this region. Its optimization lead to the more potent compound 4, which inhibits endocellular CK2, significantly affects viability of tumour cells and shows remarkable selectivity on a panel of 320 kinases.

PubMed: 32283296
DOI: 10.1016/j.ejmech.2020.112267

実験手法

X-RAY DIFFRACTION (1.54 Å)