AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Bancet, A.; Frem, R.; Jeanneret, F.; Mularoni, A.; Bazelle, P.; Roelants, C.; Delcros, J.-G.; Guichou, J.-F.; Pillet, C.; Coste, I.; Renno, T.; Battail, C.; Cochet, C.; Lomberget, T.; Filhol, O.; Krimm, I.

doi:10.1101/2022.12.16.520736

bioRxiv · 10.1101/2022.12.16.520736

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Bancet, A.·Frem, R.·Jeanneret, F.·Mularoni, A.·Bazelle, P.·Roelants, C.·Delcros, J.-G.·Guichou, J.-F.·Pillet, C.·Coste, I.·Renno, T.·Battail, C.·Cochet, C.·Lomberget, T.·Filhol, O.·Krimm, I.

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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 explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric D pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 D pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

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Bancet, A., Frem, R., Jeanneret, F., Mularoni, A., Bazelle, P., Roelants, C., Delcros, J.-G., Guichou, J.-F., Pillet, C., Coste, I., Renno, T., Battail, C., Cochet, C., Lomberget, T., Filhol, O., Krimm, I.. 2022-12-16. AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1. https://doi.org/10.1101/2022.12.16.520736

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