Publication

Article Metrics

Citations


Online attention

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 (The Institute of Cancer Research) , Isaac Westwood (The Institute of Cancer Research) , Kathy Boxall (The Institute of Cancer Research) , Nathan Brown (The Institute of Cancer Research) , Sam Peacock (The Institute of Cancer Research) , Craig Mcandrews (The Institute of Cancer Research) , Elaine Barrie (The Institute of Cancer Research) , Meirion Richards (The Institute of Cancer Research) , Amin Mirza (The Institute of Cancer Research) , Antony W. Oliver (The Institute of Cancer Research) , Rosemary Burke (The Institute of Cancer Research) , Swen Hoelder (The Institute of Cancer Research) , Keith Jones (The Institute of Cancer Research) , G. Wynne Aherne (The Institute of Cancer Research) , Julian Blagg (The Institute of Cancer Research) , Ian Collins (The Institute of Cancer Research) , Michelle D. Garrett (The Institute of Cancer Research) , Rob L. M. Van Montfort (The Institute of Cancer Research)
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, Medicine


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

Added On: 20/06/2013 15:08

Documents:
file-3.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)