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Fragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2

DOI: 10.1371/journal.pone.0065689 DOI Help
PMID: 23776527 PMID Help

Authors: Cris Silva-santisteban (Institute of Cancer Research) , Isaac Westwood (Institute of Cancer Research) , Kathy Boxall , Nathan Brown , Sam Peacock , Craig Mcandrews , Elaine Barrie , Meirion Richards , Amin Mirza , Antony W. Oliver (Cancer Research UK DNA Repair Enzyme Group) , Rosemary Burke , Swen Hoelder (Institute of Cancer Research) , Keith Jones , G. Wynne Aherne , Julian Blagg , Ian Collins , Michelle D. Garrett , Rob L.m. Van Montfort (Institute of Cancer Research, Haddow Laboratories, Sutton, Chester Beatty Laboratories, Chelsea, London) , Qiming Jane Wang
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos One , VOL 8 (6)

State: Published (Approved)
Published: June 2013

Open Access Open Access

Abstract: Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragmentbased screening campaign using a combination of a high-concentration AlphaScreenTM kinase assay and a biophysical thermal shift assay, followed by X-ray crystallography, identified a number of chemically different ligand-efficient CHK2 hinge-binding scaffolds that have not been exploited in known CHK2 inhibitors. In addition, it showed that the use of these orthogonal techniques allowed efficient discrimination between genuine hit matter and false positives from each individual assay technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based fragment and its follow-up compound highlight a hydrophobic area above the hinge region not previously explored in rat

Journal Keywords: Binding; Checkpoint; Crystallography ; Crystallography ; X-Ray ; Models ; Molecular ; Protein; Protein Kinase Inhibitors

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography