2. Academic Validation
  3. 7,7'-Diazaindirubin--a small molecule inhibitor of casein kinase 2 in vitro and in cells

7,7'-Diazaindirubin--a small molecule inhibitor of casein kinase 2 in vitro and in cells

  • Bioorg Med Chem. 2014 Jan 1;22(1):247-55. doi: 10.1016/j.bmc.2013.11.031.
Xinlai Cheng 1,  Karl-Heinz Merz 2,  Sandra Vatter 2,  Jochen Christ 2,  Stefan Wölfl 3,  Gerhard Eisenbrand 2
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Str. 52, D-67663 Kaiserslautern, Germany.
  • 3 Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
PMID: 24326279 DOI: 10.1016/j.bmc.2013.11.031
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.

Keywords

Antitumor agents; Apoptosis; Azaindirubin; Kinase profiling; Selective casein kinase inhibitor.

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