Protein kinase CK2 inhibition is associated with the destabilization of HIF-1α in human cancer cells

Cancer Lett. 2015 Jan 28;356(2 Pt B):751-61. doi: 10.1016/j.canlet.2014.10.026. Epub 2014 Oct 28.


Screening for protein kinase CK2 inhibitors of the structural diversity compound library (DTP NCI/NIH) led to the discovery of 4-[(E)-(fluoren-9-ylidenehydrazinylidene)-methyl]benzoic acid (E9). E9 induces apoptotic cell death in various cancer cell lines and upon hypoxia, the compound suppresses CK2-catalyzed HSP90/Cdc37 phosphorylation and induces HIF-1α degradation. Furthermore, E9 exerts a strong anti-tumour activity by inducing necrosis in murine xenograft models underlining its potential to be used for cancer treatment in future clinical studies. Crystal structure analysis of human and maize CK2α in complex with E9 reveals unique binding properties of the inhibitor to the enzyme, accounting for its affinity and selectivity.

Keywords: HIF-1α; Kinase inhibitors; Murine xenograft; Protein kinase CK2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / pharmacology*
  • Blotting, Western
  • Casein Kinase II / antagonists & inhibitors*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Combinatorial Chemistry Techniques
  • Female
  • Fluorenes / pharmacology*
  • Fluorescent Antibody Technique
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunoenzyme Techniques
  • Luciferases / metabolism
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Conformation / drug effects*
  • Protein Kinase Inhibitors / pharmacology*
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • 4-((fluoren-9-ylidenehydrazinylidene)methyl)benzoic acid
  • Benzoates
  • Fluorenes
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protein Kinase Inhibitors
  • Luciferases
  • Casein Kinase II