Isoform specific inhibition of human protein kinase CK2α and CK2α’ by an indenoindole derivative

The human protein kinase CK2 is an emerging target not only in current cancer research but also in the pathophysiology of viral diseases, such as CoV-2 infection. Two isoforms of the catalytic subunit of human CK2, namely CK2α and CK2α’ were identified, exhibiting high similarity but minor functional and structural differences. Further, they differ in their expression profiles, with CK2α being ubiquitously expressed in every tissue while CK2α’ being mainly present in brain and testis. In the cell, CK2α and CK2α’ exist either as free subunits or in a tetrameric complex bound to a dimer of non-catalytic CK2β subunits. Inhibitors of CK2 which selectively target specific subunits of the kinase are advantageous for the examination of the different functions of the paralogous isoforms.

Here we report on THN27B, an indeno[1,2-b]indole derivate that exhibits higher CK2α’ inhibitory activity (IC₅₀ = 0.25 µM) in comparison to CK2α (IC₅₀ = 0.61 µM). Co-crystal structures of CK2α and CK2α’ with THN27B reveled a different conformational viability in the interdomain hinge region explaining this behavior. Remarkably, this selective inhibitory behavior was eliminated by the addition of the regulatory subunit (CK2α₂β₂ IC₅₀ = 0.12 µM; CK2α’₂β₂ IC₅₀ = 0.12 µM). These results indicate that the preference of THN27B for CK2α’ can be further utilized to study the distinct functions of free catalytic subunit paralogs.