title: Protein kinase CK2 inhibition is associated with the destabilization of HIF-1α in human cancer cells.
abstract: 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.
authors.affiliation: Biomedical Research Group, BMB, University of Southern Denmark, Odense, Denmark.
authors.forename: Barbara
authors.initials: B
authors.lastname: Guerra
authors.affiliation: Biomedical Research Group, BMB, University of Southern Denmark, Odense, Denmark.
authors.forename: Tine D L
authors.initials: TD
authors.lastname: Rasmussen
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schnitzler
authors.affiliation: Biomedical Research Group, BMB, University of Southern Denmark, Odense, Denmark.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Jensen
authors.affiliation: KinaseDetect Aps, Odense, Denmark.
authors.forename: Brigitte S
authors.initials: BS
authors.lastname: Boldyreff
authors.affiliation: Department of Cell & Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Miyata
authors.affiliation: Institute of Pathology, OUH, Odense, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, Cologne, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Niefind
authors.affiliation: Biomedical Research Group, BMB, University of Southern Denmark, Odense, Denmark; KinaseDetect Aps, Odense, Denmark. Electronic address: ogi@bmb.sdu.dk.
authors.forename: Olaf-Georg
authors.initials: OG
authors.lastname: Issinger
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D005260:Female; D005449:Fluorenes / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595660:4-((fluoren-9-ylidenehydrazinylidene)methyl)benzoic acid; D001565:Benzoates; D005449:Fluorenes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D008156:Luciferases; D047390:Casein Kinase II
keywords: HIF-1α; Kinase inhibitors; Murine xenograft; Protein kinase CK2