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

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; Isabelle Krimm

doi:10.1016/j.isci.2024.108903

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

iScience. 2024 Jan 12;27(2):108903. doi: 10.1016/j.isci.2024.108903. eCollection 2024 Feb 16.

Authors

Alexandre Bancet^{1

2}, Rita Frem³, Florian Jeanneret⁴, Angélique Mularoni¹, Pauline Bazelle⁴, Caroline Roelants⁵, Jean-Guy Delcros¹, Jean-François Guichou⁶, Catherine Pillet⁵, Isabelle Coste³, Toufic Renno³, Christophe Battail⁴, Claude Cochet⁵, Thierry Lomberget⁷, Odile Filhol⁵, Isabelle Krimm¹

Affiliations

¹ University Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Institut Convergence Plascan, Team « Small Molecules for Biological Targets », 69373 Lyon, France.
² Kairos Discovery SAS, 36 Rue Jeanne d'Arc, 69003 Lyon, France.
³ University Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Institut Convergence Plascan, Team « Targeting Non-canonical Protein Functions in Cancer », 69373 Lyon, France.
⁴ Université Grenoble Alpes, IRIG, Laboratoire Biosciences et Bioingénierie pour la Santé, UA 13 INSERM-CEA-UGA, 38000 Grenoble, France.
⁵ University Grenoble Alpes, INSERM 1292, CEA, UMR Biosanté, 38000 Grenoble, France.
⁶ Centre de Biologie Structurale, CNRS, INSERM, University Montpellier, 34090 Montpellier, France.
⁷ University Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5246, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), COSSBA Team, Faculté de Pharmacie-ISPB, 8 Avenue Rockefeller, 69373 Lyon Cedex 08, France.

Abstract

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.

Keywords: Cancer; Cell biology; Molecular biology; Structural biology.