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Specific inhibition of CK2α from an anchor outside the active site

DOI: 10.1039/C6SC02335E DOI Help

Authors: Paul Brear (University of Cambridge) , Claudia De Fusco (University of Cambridge) , Kathy Hadje Georgiou (University of Cambridge) , Nicola J. Francis-newton (University of Cambridge) , Christopher J. Stubbs (University of Cambridge) , Hannah F. Sore (University of Cambridge) , Ashok R. Venkitaraman (University of Cambridge) , Chris Abell (University of Cambridge) , David R. Spring (University of Cambridge) , Marko Hyvonen (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chem. Sci.

State: Published (Approved)
Published: July 2016
Diamond Proposal Number(s): 9007 , 9537 , 14043

Open Access Open Access

Abstract: 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.

Journal Keywords: Fragment based screening

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


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: ESRF

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