5N9L

Crystal structure of human Protein kinase CK2 catalytic subunit in complex with the ATP-competitive dibenzofuran inhibitor TF (4b)

Summary for 5N9L

• Entry DOI: 10.2210/pdb5n9l/pdb
• Related: 5N9K 5N9N
• Descriptor: Casein kinase II subunit alpha, (4~{Z})-6,7-bis(chloranyl)-4-[[(4-methylphenyl)amino]methylidene]-8-oxidanyl-1,2-dihydrodibenzofuran-3-one, ACETATE ION, ... (5 entities in total)
• Functional Keywords: protein kinase, ck2, casein kinase 2, protein phosphorylation, atp-competitive inhititors, dibenzofuran derivatives, transferase, tight-binding inhibitors
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P68400
• Total number of polymer chains: 1
• Total formula weight: 40941.45

Authors

Schnitzler, A.,Gratz, A.,Bollacke, A.,Weyrich, M.,Kucklaender, U.,Wuensch, B.,Goetz, C.,Niefind, K.,Jose, J. (deposition date: 2017-02-25, release date: 2018-02-28, Last modification date: 2024-01-17)

Primary citation

Schnitzler, A.,Gratz, A.,Bollacke, A.,Weyrich, M.,Kucklander, U.,Wunsch, B.,Gotz, C.,Niefind, K.,Jose, J.
A pi-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors.
Pharmaceuticals, 11:-, 2018

PubMed Abstract: Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[,]furan-3(2)-one () and ()-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[,]furan-2,7-diol () were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC values of 7 nM () and 5 nM () and an apparent K value of 0.4 nM for both. Compounds and reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of and revealed an unexpected -halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound , with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency.

PubMed: 29462988
DOI: 10.3390/ph11010023

Experimental method

X-RAY DIFFRACTION (1.79 Å)