Universität zu Köln

Lindenblatt, Dirk ORCID: 0000-0002-5561-1082, Applegate, Violetta ORCID: 0000-0003-4120-7983, Nickelsen, Anna, Klussmann, Merlin, Neundorf, Ines, Goetz, Claudia, Jose, Joachim ORCID: 0000-0002-0666-2676 and Niefind, Karsten ORCID: 0000-0002-0183-6315 (2022). Molecular Plasticity of Crystalline CK2 alpha ' Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity. J. Med. Chem., 65 (2). S. 1302 - 1313. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

CK2a and CK2 alpha' are paralogous catalytic subunits of CK2, which belongs to the eukaryotic protein kinases. CK2 promotes tumorigenesis and the spread of pathogenic viruses like SARS-CoV-2 and is thus an attractive drug target. Efforts to develop selective CK2 inhibitors binding offside the ATP site had disclosed the alpha D pocket in CK2 alpha; its occupation requires large conformational adaptations of the helix alpha D. As shown here, the alpha D pocket is accessible also in CK2 alpha', where the necessary structural plasticity can be triggered with suitable ligands even in the crystalline state. A CK2 alpha' structure with an ATP site and an aD pocket ligand guided the design of the bivalent CK2 inhibitor KN2. It binds to CK2 with low nanomolar affinity, is cell-permeable, and suppresses the intracellular phosphorylation of typical CK2 substrates. Kinase profiling revealed a high selectivity of KN2 for CK2 and emphasizes the selectivity-promoting potential of the alpha D pocket.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lindenblatt, Dirk UNSPECIFIED orcid.org/0000-0002-5561-1082 UNSPECIFIED Applegate, Violetta UNSPECIFIED orcid.org/0000-0003-4120-7983 UNSPECIFIED Nickelsen, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Klussmann, Merlin UNSPECIFIED UNSPECIFIED UNSPECIFIED Neundorf, Ines UNSPECIFIED UNSPECIFIED UNSPECIFIED Goetz, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Jose, Joachim UNSPECIFIED orcid.org/0000-0002-0666-2676 UNSPECIFIED Niefind, Karsten UNSPECIFIED orcid.org/0000-0002-0183-6315 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-672820
DOI:	10.1021/acs.jmedchem.1c00063
Journal or Publication Title:	J. Med. Chem.
Volume:	65
Number:	2
Page Range:	S. 1302 - 1313
Date:	2022
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-4804
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CATALYTIC SUBUNIT; DISCOVERY; INSIGHTS; BINDING; ASSAY Multiple languages Chemistry, Medicinal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67282