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

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Bancet, Alexandre | Frem, Rita | Jeanneret, Florian | Mularoni, Angélique | Bazelle, Pauline | Roelants, Caroline | Delcros, Jean-Guy | Guichou, Jean-François | Pillet, Catherine | Coste, Isabelle | Renno, Toufic | Battail, Christophe | Cochet, Claude | Lomberget, Thierry | Filhol, Odile | Krimm, Isabelle

Edité par CCSD ; Elsevier -

International audience. 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 αD 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, CX-4945, and SGC-CK2-1. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668, by targeting the CK2 αD 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

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