Molecular Plasticity of Crystalline CK2α′ Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity

CK2α and CK2α′
are paralogous catalytic subunits
of CK2, which belongs to the eukaryotic protein kinases. CK2 promotes
tumorigenesis and the spread of pathogenic viruses like SARS-CoV-2
and is thus an attractive drug target. Efforts to develop selective
CK2 inhibitors binding offside the ATP site had disclosed the αD
pocket in CK2α; its occupation requires large conformational
adaptations of the helix αD. As shown here, the αD pocket
is accessible also in CK2α′, where the necessary structural
plasticity can be triggered with suitable ligands even in the crystalline
state. A CK2α′ structure with an ATP site and an αD
pocket ligand guided the design of the bivalent CK2 inhibitor KN2.
It binds to CK2 with low nanomolar affinity, is cell-permeable, and
suppresses the intracellular phosphorylation of typical CK2 substrates.
Kinase profiling revealed a high selectivity of KN2 for CK2 and emphasizes
the selectivity-promoting potential of the αD pocket.