Please use this identifier to cite or link to this item: doi:10.22028/D291-29388
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Title: 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site
Author(s): Bestgen, Benoît
Krimm, Isabelle
Kufareva, Irina
Kamal, Ahmed Ashraf Moustafa
Seetoh, Wei-Guang
Abell, Chris
Hartmann, Rolf W.
Abagyan, Ruben
Cochet, Claude
Le Borgne, Marc
Engel, Matthias
Lomberget, Thierry
Language: English
Title: Journal of medicinal chemistry
Volume: 62
Issue: 4
Startpage: 1803
Endpage: 1816
Publisher/Platform: American Chemical Society (ACS)
Year of Publication: 2019
Publikation type: Journal Article
Abstract: CK2 is a ubiquitous Ser/Thr protein kinase involved in the control of various signaling pathways and is known to be constitutively active. In the present study, we identified aryl 2-aminothiazoles as a novel class of CK2 inhibitors, which displayed a non-ATP-competitive mode of action and stabilized an inactive conformation of CK2 in solution. Enzyme kinetics studies, STD NMR, circular dichroism spectroscopy, and native mass spectrometry experiments demonstrated that the compounds bind in an allosteric pocket outside the ATP-binding site. Our data, combined with molecular docking studies, strongly suggested that this new binding site was located at the interface between the αC helix and the flexible glycine-rich loop. A first hit optimization led to compound 7, exhibiting an IC50 of 3.4 μM against purified CK2α in combination with a favorable selectivity profile. Thus, we identified a novel class of CK2 inhibitors targeting an allosteric pocket, offering great potential for further optimization into anticancer drugs.
DOI of the first publication: 10.1021/acs.jmedchem.8b01766
Link to this record: hdl:20.500.11880/27870
ISSN: 0022-2623
Date of registration: 24-Sep-2019
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Christian Ducho
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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