2‑Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site

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.