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A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066

DOI: 10.1016/j.bmc.2017.04.037 DOI Help

Authors: Claudia De Fusco (University of Cambridge) , Paul Brear (University of Cambridge) , Jessica Iegre (University of Cambridge) , Kathy Hadje Georgiou (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: April 2017
Diamond Proposal Number(s): 9537 , 9007

Abstract: Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.

Journal Keywords: CK2; Fragment-based drug discovery; Kinase inhibition; Fragment linking: Molecular modelling

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


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

Other Facilities: SOLEIL

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