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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|
Hartmann, Rolf W.
Le Borgne, Marc
|Title:||Journal of medicinal chemistry|
|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|
|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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