SGC-CK2-1

There is a disconnect in the linked publication between the NanoBret cellular IC50 of 16-36 nM and the apparent functional IC50 of inhibiting AKT S129 phosphorylation that appears to be ~500 nM.  It is unclear then if the lack of activity as an antiproliferative for which CK2 inhibitors have been claimed as a result of weaker cellular activity than NanoBret estimates or off-target pharmacology of previous tools as the authors suggest.  Consistent with this concern, the previously reported enzymatic potency (presumably measured near the Km of ATP) of compounds 16 and 29 are near equipotent with the in-cell NanoBret potencies reported here, which is unlikely in that multimillimolar ATP in cells surely competes with an ATP-competitive ligand.  Finally, it is unclear if the reported compound (24) is truly more selective than the previously reported compound 22, which by NanoBret is an order of magnitude more potent.  Selectivity based on the % of kinases inhibited by a threshold amount at a fixed concentration will always favor the weaker compound.

SGC-CK2-1 is a valuable probe for interrogating the cellular effects of CK2 inhibition, as it is considerably more selective against related kinases such as DYRK2 than previously reported inhibitors of this kinase including CX-4945. In addition to having excellent cellular and biochemical activity, SGC-CK2-1 has a structurally related negative control available that helps further support target validation. SGC-CK2-1 is active in two orthogonal cellular assays, cellular inhibition of pAKT and nanobret target engagement assay. Although its selectivity over other kinases is excellent, it is of similar potency against CK2a and CK2a’. It appears to have excellent cellular penetration based on its published target engagement data and anti-proliferative activities in one cell line. Although it possesses modest biochemical activity against DYRK2, it has no activity against DYRK2 in the nanobret assay. The pharmacokinetics and ADME properties of SGC-CK2-1 have not yet been interrogated, so no in vivo target validation/activity studies are advised until further profiling has been done.