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Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2.

Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C, Barrie E, Richards M, Mirza A, Oliver AW, Burke R, Hoelder S, Jones K, Aherne GW, Blagg J, Collins I, Garrett MD, van Montfort RL
PLoS One 8 e65689 (2013)
Related entries: 4bda, 4bdb, 4bdc, 4bdd, 4bde, 4bdf, 4bdg, 4bdh, 4bdi, 4bdk

Cited: 5 times
EuropePMC logo PMID: 23776527

Abstract

Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragment-based screening campaign using a combination of a high-concentration AlphaScreen™ 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 rational CHK2 inhibitor design, but which might be exploited to enhance both potency and selectivity of CHK2 inhibitors.

Articles - 4bdj mentioned but not cited (2)

  1. Structure-activity relationships of fraxamoside as an unusual xanthine oxidase inhibitor. Vitale RM, Antenucci L, Gavagnin M, Raimo G, Amodeo P. J Enzyme Inhib Med Chem 32 345-354 (2017)
  2. Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2. Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C, Barrie E, Richards M, Mirza A, Oliver AW, Burke R, Hoelder S, Jones K, Aherne GW, Blagg J, Collins I, Garrett MD, van Montfort RL. PLoS One 8 e65689 (2013)


Reviews citing this publication (2)

  1. Structure-based drug design: aiming for a perfect fit. van Montfort RLM, Workman P. Essays Biochem 61 431-437 (2017)
  2. The hunt for antimitotic agents: an overview of structure-based design strategies. Dube D, Tiwari P, Kaur P. Expert Opin Drug Discov 11 579-597 (2016)

Articles citing this publication (1)

  1. Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase. Pollock K, Liu M, Zaleska M, Meniconi M, Pfuhl M, Collins I, Guettler S. Sci Rep 9 19130 (2019)


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