Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Pietsch, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Viht, Kaido UNSPECIFIED UNSPECIFIED UNSPECIFIED Schnitzler, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Ekambaram, Ramesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinkrueger, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Enkvist, Erki UNSPECIFIED UNSPECIFIED UNSPECIFIED Nienberg, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Nickelsen, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Lauwers, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Jose, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Uri, Asko UNSPECIFIED UNSPECIFIED UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Inorganic Chemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CRYSTAL-STRUCTURE; CK2-ALPHA; BINDING; DESIGN; ASSAY; SUBUNIT; CELLS Multiple languages Biochemistry & Molecular Biology; Chemistry, Organic Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/34259