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

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dc.creatorDe Fusco, C
dc.creatorBrear, P
dc.creatorIegre, J
dc.creatorGeorgiou, KH
dc.creatorSore, HF
dc.creatorHyvönen, M
dc.creatorSpring, DR
dc.date2017-08-15T10:49:12Z
dc.date2017-08-15T10:49:12Z
dc.date2017-07-01
dc.date.accessioned2026-08-03T02:45:13Z
dc.descriptionRecently 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.
dc.descriptionThis 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.
dc.formatapplication/pdf
dc.identifier0968-0896
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/266383
dc.identifier10.17863/CAM.12614
dc.identifier1464-3391
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/168884
dc.languageeng
dc.languageeng
dc.publisherElsevier
dc.publisherhttps://doi.org/10.1016/j.bmc.2017.04.037
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCK2
dc.subjectFragment-based drug discovery
dc.subjectKinase inhibition
dc.subjectFragment linking
dc.subjectMolecular modelling
dc.titleA fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066
dc.typeArticle

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