Pietsch, Markus, Viht, Kaido, Schnitzler, Alexander, Ekambaram, Ramesh, Steinkrueger, Michaela, Enkvist, Erki, Nienberg, Christian, Nickelsen, Anna, Lauwers, Miriam, Jose, Joachim, Uri, Asko and Niefind, Karsten ORCID: 0000-0002-0183-6315 (2020). Unexpected CK2 beta-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2. Bioorganic Chem., 96. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1090-2120

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Abstract

Protein kinase CK2, a heterotetrameric holoenzyme composed of two catalytic chains (CK2 alpha) attached to a homodimer of regulatory subunits (CK2 beta), is a target for drug development for cancer therapy. Here, we describe the tetraiodobenzimidazole derivative ARC-3140, a bisubstrate inhibitor addressing the ATP site and the substrate-binding site of CK2 with extraordinary affinity (K-i = 84 pM). In a crystal structure of ARC-3140 in complex with CK2 alpha, three copies of the inhibitor are visible, one of them at the CK2 beta interface of CK2 alpha. Subsequent interaction studies based on microscale thermophoresis and fluorescence anisotropy changes revealed a significant impact of ARC-3140 and of its tetrabromo equivalent ARC-1502 on the CK2 alpha/CK2 beta interaction. A structural inspection revealed that ARC-3140, unlike CK2 beta antagonists described so far, interferes with both sub-interfaces of the bipartite CK2 alpha/CK2 beta interaction. Thus, ARC-3140 is a lead for the further development of highly effective compounds perturbating the quaternary structure of the CK2 alpha(2)beta(2) holoenzyme.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pietsch, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viht, KaidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schnitzler, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ekambaram, RameshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinkrueger, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Enkvist, ErkiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nienberg, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickelsen, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauwers, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jose, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uri, AskoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niefind, KarstenUNSPECIFIEDorcid.org/0000-0002-0183-6315UNSPECIFIED
URN: urn:nbn:de:hbz:38-342594
DOI: 10.1016/j.bioorg.2020.103608
Journal or Publication Title: Bioorganic Chem.
Volume: 96
Date: 2020
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication: SAN DIEGO
ISSN: 1090-2120
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CRYSTAL-STRUCTURE; CK2-ALPHA; BINDING; DESIGN; ASSAY; SUBUNIT; CELLSMultiple languages
Biochemistry & Molecular Biology; Chemistry, OrganicMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34259

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