title: 7,7'-Diazaindirubin--a small molecule inhibitor of casein kinase 2 in vitro and in cells.
abstract: Aza- and diaza-bisindoles were synthesized by coupling of 7-azaisatin, 7-azaoxindol, 7-azaindoxyl acetate, and their non-aza counterparts, respectively. Whereas 7,7'-diazaindigo (10) and 7,7'-diazaisoindigo (11) did not show antiproliferative activity in several human tumor cell lines up to 100 μM, 7-azaindirubin (12) and 7'-azaindirubin (13) were more active than the parent molecule, indirubin, in LXFL529L cells (human large cell lung tumor xenograft), and 7,7'-diazaindirubin (14) was exhibiting substantially enhanced growth inhibitory activity in these cells. In the NCI 60 cell line panel, 14 displayed antiproliferative activity preferentially in certain melanoma and non-small cell lung cancer cells. In contrast to the potent serine/threonine/tyrosine kinase inhibition observed for indirubins, kinase inhibition profiling of 14 in 220 kinases revealed largely a loss of kinase inhibitory activity towards most kinases, with retained inhibitory activity for just a few kinases. At 1 μM concentration, especially casein kinases CK1γ3, CK2α, CK2α2, and SIK were inhibited by more than 50%. In cell-based assays, 14 markedly affected CK2-mediated signaling in various human tumor cells. In MCF7 cells, 14 induced cell cycle arrest at G1 and G2/M and apoptosis, whereas CK2-deficient MCF7 cells were resistant. These findings reveal a novel key mechanism of action for 14, suggesting primarily CK2 inhibition to be causally related to growth inhibition of human tumor cells.
authors: Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, D-67663 Kaiserslautern, Germany; Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany. Electronic address: x.cheng@uni-heidelberg.de.
authors: Xinlai
authors: X
authors: Cheng
authors: Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, D-67663 Kaiserslautern, Germany.
authors: Karl-Heinz
authors: KH
authors: Merz
authors: Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, D-67663 Kaiserslautern, Germany.
authors: Sandra
authors: S
authors: Vatter
authors: Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, D-67663 Kaiserslautern, Germany.
authors: Jochen
authors: J
authors: Christ
authors: Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Wölfl
authors: Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, D-67663 Kaiserslautern, Germany.
authors: Gerhard
authors: G
authors: Eisenbrand
mesh_terms: D017209:Apoptosis; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection
chemical_list: D047390:Casein Kinase II
keywords: Antitumor agents; Apoptosis; Azaindirubin; Kinase profiling; Selective casein kinase inhibitor