8QQB

Crystal structure of protein kinase CK2 catalytic subunit in complex with a Dibromo Dihydro Dibenzofuranone derivative

Summary for 8QQB

• Entry DOI: 10.2210/pdb8qqb/pdb
• Descriptor: Casein kinase II subunit alpha, 1,2-ETHANEDIOL, (4~{Z})-7,9-bis(bromanyl)-8-oxidanyl-4-(phenylazanylmethylidene)-1,2-dihydrodibenzofuran-3-one, ... (5 entities in total)
• Functional Keywords: protein kinase ck2 casein kinase ii catalytic subunit ck2alpha dibenzofuranone inhibitors, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 85251.80

Authors

Werner, C.,Niefind, K.,Jose, J. (deposition date: 2023-10-04, release date: 2024-10-16, Last modification date: 2025-01-01)

Primary citation

Rumler, H.,Schmithals, C.,Werner, C.,Bollacke, A.,Aichele, D.,Gotz, C.,Niefind, K.,Wunsch, B.,Jose, J.
Discovery of 7,9-Dibromo-dihydrodibenzofuran as a Potent Casein Kinase 2 (CK2) Inhibitor: Synthesis, Biological Evaluation, and Structural Studies on E- / Z -Isomers.
Acs Pharmacol Transl Sci, 7:3846-3866, 2024

PubMed Abstract: The human protein kinase CK2 is a promising target for cancer treatment. Only two CK2 inhibitors have reached clinical trials until today. Among others, a dibenzofuran scaffold has emerged as highly prospective for the development of new CK2 inhibitors. Thirty-three newly synthesized dibenzofuran-based compounds were tested on their inhibitory potential . 7,9-Dichloro-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[,]furan-3(4)-one () and 7,9-dibromo-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[,]furan-3(4)-one () showed the lowest IC values with 5.8 nM for both. The dibenzofuran-based CK2 inhibitors crossed the cell membrane of LNCaP human prostate carcinoma cells and reduced intracellular CK2 activity. Among 70 kinases from different representative subgroups of the human kinome, CK2 was most strongly inhibited by compound . Co-crystallization of together with CK2α indicated a π-halogen bond of the bromine at position C9 with the gatekeeper amino acid Phe113. CK2α could bind both the - and -isomers of . Our results provide new insights into the structure-activity relationships of dibenzofuran derivatives.

PubMed: 39698287
DOI: 10.1021/acsptsci.4c00426

Experimental method

X-RAY DIFFRACTION (2.26 Å)