1. Cancer selective cell death induction by a bivalent CK2 inhibitor targeting the ATP site and the allosteric αD pocket
- Author
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Alexandre Bancet, Rita Frem, Florian Jeanneret, Angélique Mularoni, Pauline Bazelle, Caroline Roelants, Jean-Guy Delcros, Jean-François Guichou, Catherine Pillet, Isabelle Coste, Toufic Renno, Christophe Battail, Claude Cochet, Thierry Lomberget, Odile Filhol, and Isabelle Krimm
- Subjects
Molecular biology ,Cell biology ,Structural biology ,Cancer ,Science - Abstract
Summary: 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.
- Published
- 2024
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