Novel non-ATP competitive small molecules targeting the CK2 α/β interface

DOI: 10.1016/j.bmc.2018.05.011

Authors: Paul Brear (University of Cambridge) , Andrew North (University of Cambridge) , Jessica Iegre (University of Cambridge) , Kathy Hadje Georgiou (University of Cambridge) , Alexandra Lubin (University of Cambridge) , Laura Carro (University of Cambridge) , William Green (University of Cambridge) , Hannah F. Sore (University of Cambridge) , Marko Hyvonen (University of Cambridge) , David R. Spring (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 9537

Abstract: 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.

Journal Keywords: CK2; Protein-protein interaction; Fragment based drug discovery

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF

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