Unexpected CK2β-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2

Markus Pietsch; Kaido Viht; Alexander Schnitzler; Ramesh Ekambaram; Michaela Steinkrüger; Erki Enkvist; Christian Nienberg; Anna Nickelsen; Miriam Lauwers; Joachim Jose; Asko Uri; Karsten Niefind

doi:10.1016/j.bioorg.2020.103608

Unexpected CK2β-antagonistic functionality of bisubstrate inhibitors targeting protein kinase CK2

Bioorg Chem. 2020 Mar:96:103608. doi: 10.1016/j.bioorg.2020.103608. Epub 2020 Jan 23.

Authors

Affiliations

¹ Institut II für Pharmakologie, Zentrum für Pharmakologie, Medizinische Fakultät, Universität zu Köln, Gleueler Str. 24, D-50931 Köln, Germany.
² Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia.
³ Institut für Biochemie, Department für Chemie, Universität zu Köln, Zülpicher Str. 47, D-50674 Köln, Germany.
⁴ Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, PharmaCampus, Corrensstr. 48, D-48149 Münster, Germany.
⁵ Institute of Chemistry, University of Tartu, 14A Ravila St., 50411 Tartu, Estonia. Electronic address: Asko.Uri@ut.ee.
⁶ Institut für Biochemie, Department für Chemie, Universität zu Köln, Zülpicher Str. 47, D-50674 Köln, Germany. Electronic address: Karsten.Niefind@uni-koeln.de.

PMID: 32058103
DOI: 10.1016/j.bioorg.2020.103608

Abstract

Protein kinase CK2, a heterotetrameric holoenzyme composed of two catalytic chains (CK2α) attached to a homodimer of regulatory subunits (CK2β), 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 CK2α, three copies of the inhibitor are visible, one of them at the CK2β interface of CK2α. 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 CK2α/CK2β interaction. A structural inspection revealed that ARC-3140, unlike CK2β antagonists described so far, interferes with both sub-interfaces of the bipartite CK2α/CK2β interaction. Thus, ARC-3140 is a lead for the further development of highly effective compounds perturbating the quaternary structure of the CK2α₂β₂ holoenzyme.

Keywords: Bisubstrate inhibitor; CK2β antagonists; Capillary electrophoresis-based kinase assay; Fluorescence anisotropy assay; Microscale thermophoresis; Protein kinase CK2; Protein/protein interaction; X-ray crystallography.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzimidazoles / chemistry*
Benzimidazoles / pharmacology*
Casein Kinase II / antagonists & inhibitors*
Casein Kinase II / chemistry
Casein Kinase II / metabolism
Catalytic Domain / drug effects
Crystallography, X-Ray
Halogenation
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Multimerization / drug effects
Protein Structure, Quaternary / drug effects
Protein Subunits / antagonists & inhibitors
Protein Subunits / chemistry
Protein Subunits / metabolism

Substances

Benzimidazoles
Protein Kinase Inhibitors
Protein Subunits
CSNK2A1 protein, human
Casein Kinase II