Specific inhibition of CK2α from an anchor outside the active site.
De Fusco, Claudia
Hadje Georgiou, Kathy
Francis-Newton, Nicola J
Stubbs, Christopher J
Royal Society of Chemistry (RSC)
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Brear, P., De Fusco, C., Hadje Georgiou, K., Francis-Newton, N. J., Stubbs, C. J., Sore, H., Venkitaraman, A., et al. (2016). Specific inhibition of CK2α from an anchor outside the active site.. Chem Sci, 6839-6845. https://doi.org/10.1039/c6sc02335e
The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a Kd of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α via a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.
This work was funded by the Wellcome Trust Strategic (090340/Z/09/Z) and Pathfinder (107714/Z/15/Z) Awards, the Engineering and Physical Sciences Research Council and the European Research Council (279337/ DOS). Work in ARV's laboratory is supported by the UK Medical Research Council (Program G1001522 & grant-in-aid to the MRC Cancer Unit). CD thanks the Herchel Smith Funds for a postdoctoral fellowship.
Royal Society (WM150022)
European Research Council (279337)
Engineering and Physical Sciences Research Council (EP/J016012/1)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Medical Research Council (G1001522)
Wellcome Trust (090340/Z/09/Z)
Wellcome Trust (107714/Z/15/Z)
External DOI: https://doi.org/10.1039/c6sc02335e
This record's URL: https://www.repository.cam.ac.uk/handle/1810/257340
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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