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

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.