5H8B

Crystal structure of CK2 with compound 2

Summary for 5H8B

• Entry DOI: 10.2210/pdb5h8b/pdb
• Related: 5H8E 5H8G
• Descriptor: Casein kinase II subunit alpha, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, ck2, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P68400
• Total number of polymer chains: 2
• Total formula weight: 83060.11

Authors

Ferguson, A.D. (deposition date: 2015-12-23, release date: 2016-02-10, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.55 Å)