A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066
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Peer-reviewed
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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.
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Keywords
CK2, Fragment-based drug discovery, Kinase inhibition, Fragment linking, Molecular modelling
Journal Title
Bioorganic and Medicinal Chemistry
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Journal ISSN
0968-0896
1464-3391
1464-3391
Volume Title
25
Publisher
Elsevier
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Sponsorship
Engineering and Physical Sciences Research Council (EP/J016012/1)
Wellcome Trust (090340/Z/09/Z)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Engineering and Physical Sciences Research Council (EP/P020291/1)
Wellcome Trust (107714/Z/15/Z)
European Research Council (279337)
Wellcome Trust (090340/Z/09/Z)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Engineering and Physical Sciences Research Council (EP/P020291/1)
Wellcome Trust (107714/Z/15/Z)
European Research Council (279337)
This work was funded by the Wellcome Trust Strategic (090340/Z/09/Z) and Pathfinder (107714/Z/15/Z) Awards. The Spring lab acknowledges support from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS]. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Royal Society and Welcome Trust.