Discovery of 7,9-Dibromo-dihydrodibenzofuran as a Potent Casein Kinase 2 (CK2) Inhibitor: Synthesis, Biological Evaluation, and Structural Studies on <i>E-</i>/<i>Z</i>-Isomers

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 <i>in vitro</i>. 7,9-Dichloro-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[<i>b</i>,<i>d</i>]furan-3(4<i>H</i>)-one (<b>12b</b>) and 7,9-dibromo-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[<i>b</i>,<i>d</i>]furan-3(4<i>H</i>)-one (<b>12c</b>) showed the lowest IC₅₀ 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 <b>12c</b>. Co-crystallization of <b>12c</b> 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 <i>E</i>- and <i>Z</i>-isomers of <b>12c</b>. Our results provide new insights into the structure-activity relationships of dibenzofuran derivatives.