Please use this identifier to cite or link to this item: doi:10.22028/D291-29389
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Title: 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action
Author(s): Bestgen, Benoît
Kufareva, Irina
Seetoh, Weiguang
Abell, Chris
Hartmann, Rolf W.
Abagyan, Ruben
Le Borgne, Marc
Filhol, Odile
Cochet, Claude
Lomberget, Thierry
Engel, Matthias
Language: English
Title: Journal of medicinal chemistry
Volume: 62
Issue: 4
Startpage: 1817
Endpage: 1836
Publisher/Platform: American Chemical Society (ACS)
Year of Publication: 2019
Publikation type: Journal Article
Abstract: Protein CK2 has gained much interest as an anticancer drug target in the past decade. We had previously described the identification of a new allosteric site on the catalytic α-subunit, along with first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino)benzoic acid scaffold. In the present work, structure optimizations guided by a binding model led to the identification of the lead compound 2-hydroxy-4-((4-(naphthalen-2-yl)thiazol-2-yl)amino)benzoic acid (27), showing a submicromolar potency against purified CK2α (IC50 = 0.6 μM). Furthermore, 27 induced apoptosis and cell death in 786-O renal cell carcinoma cells (EC50 = 5 μM) and inhibited STAT3 activation even more potently than the ATP-competitive drug candidate CX-4945 (EC50 of 1.6 μM vs 5.3 μM). Notably, the potencies of our allosteric ligands to inhibit CK2 varied depending on the individual substrate. Altogether, the novel allosteric pocket was proved a druggable site, offering an excellent perspective to develop efficient and selective allosteric CK2 inhibitors.
DOI of the first publication: 10.1021/acs.jmedchem.8b01765
Link to this record: hdl:20.500.11880/27871
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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