Discovery of 7,9-Dibromo-dihydrodibenzofuran\nas a\nPotent Casein Kinase 2 (CK2) Inhibitor: Synthesis, Biological Evaluation,\nand Structural Studies on <i>E‑</i>/<i>Z</i>‑Isomers

The human protein kinase CK2 is a promising target for\ncancer treatment.\nOnly two CK2 inhibitors have reached clinical trials until today.\nAmong others, a dibenzofuran scaffold has emerged as highly prospective\nfor the development of new CK2 inhibitors. Thirty-three newly synthesized\ndibenzofuran-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 IC<sub>50</sub> values with 5.8 nM\nfor both. The dibenzofuran-based CK2 inhibitors crossed the cell membrane\nof LNCaP human prostate carcinoma cells and reduced intracellular\nCK2 activity. Among 70 kinases from different representative subgroups\nof the human kinome, CK2 was most strongly inhibited by compound <b>12c</b>. Co-crystallization of <b>12c</b> together with\nCK2α indicated a π-halogen bond of the bromine at position\nC9 with the gatekeeper amino acid Phe113. CK2α could bind both\nthe <i>E</i>- and <i>Z</i>-isomers of <b>12c</b>. Our results provide new insights into the structure–activity\nrelationships of dibenzofuran derivatives.