6RCB

Human protein kinase CK2 alpha in complex with 2-cyano-2-propenamide compound 14

Summary for 6RCB

• Entry DOI: 10.2210/pdb6rcb/pdb
• Related: 6RB1
• Descriptor: Casein kinase II subunit alpha, (~{E})-2-cyano-~{N}-(2-hydroxyphenyl)-3-(3-methoxy-4-oxidanyl-phenyl)prop-2-enamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase domain, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40752.31

Authors

Dalle Vedove, A.,Lolli, G. (deposition date: 2019-04-11, release date: 2020-04-08, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.05 Å)