Open Access2-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) -
Benoît Bestgen,
Irina Kufareva,
Wei-Guang Seetoh,
Chris Abell,
Rolf W. Hartmann,
Ruben Abagyan,
Marc Le Borgne,
Odile Filhol,
Claude Cochet,
Thierry Lomberget,
Matthias Engel
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b01765
Subject(s) - allosteric regulation , chemistry , druggability , benzoic acid , drug discovery , small molecule , stereochemistry , protein subunit , biochemistry , enzyme , gene
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 (IC 50 = 0.6 μM). Furthermore, 27 induced apoptosis and cell death in 786-O renal cell carcinoma cells (EC 50 = 5 μM) and inhibited STAT3 activation even more potently than the ATP-competitive drug candidate CX-4945 (EC 50 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.