Novel non-ATP competitive small molecules targeting the CK2 α/β interface
Hadje Georgiou, Kathy
Bioorganic & Medicinal Chemistry
MetadataShow full item record
Brear, P., North, A., Iegre, J., Hadje Georgiou, K., Lubin, A., Carro, L., Green, W., et al. (2018). Novel non-ATP competitive small molecules targeting the CK2 α/β interface. Bioorganic & Medicinal Chemistry https://doi.org/10.1016/j.bmc.2018.05.011
Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2α and CK2β at the α-β interface of the holoenzyme. A fragment, CAM187, with an IC50 of 44 μM and a molecular weight of only 257 gmol-1 has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2α. The fragment-like molecules discovered in this study represent unique scaffolds to CK2 inhibition and leave room for further optimisation.
CK2, protein-protein interaction, fragment based drug discovery
This work was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS] (to DRS) and the Wellcome Trust Strategic (090340/Z/09/Z) and Pathfinder (107714/Z/15/Z) Awards (to DRS and MH). In addition, the Spring group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and the Royal Society. JI would like to thank Trinity College, University of Cambridge for funding.
WELLCOME TRUST (107714/Z/15/Z)
Wellcome Trust (090340/Z/09/Z)
European Research Council (279337)
External DOI: https://doi.org/10.1016/j.bmc.2018.05.011
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280378