Cancer selective cell death induction by a bivalent CK2 inhibitor targeting the ATP site and the allosteric aD pocket

Although the involvement of protein kinase CK2 in cancer is well -documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer -related biological pathways and further exploring its therapeutic potential. Here, we report the discovery of AB668, an outstanding selective inhibitor that binds CK2 through a bivalent mode, interacting both at the ATP site and an allosteric aD pocket unique to CK2. Using caspase activation assay, live -cell imaging, and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to representative ATP -competitive inhibitors, CX4945, and SGC-CK2-1. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668, by targeting the CK2 aD pocket, has a distinct mechanism of action regarding its anti -cancer activity, inducing apoptotic cell death in several cancer cell lines and stimulating distinct biological pathways in renal cell carcinoma.