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Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2.
journal contribution
posted on 2023-06-08, 07:36 authored by John J Caldwell, Emma J Welsh, Cornelis Matjissen, Victoria E Anderson, Laurent Antoni, Kathy Boxall, Frederique Urban, Angela Hayes, Florence I Raynaud, Laurent J M Rigoreau, Tony Raynham, G Wynne Aherne, Laurence PearlLaurence Pearl, Antony OliverAntony Oliver, Michelle D Garrett, Ian CollinsStructure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structureactivity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC50 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).
History
Publication status
- Published
Journal
Journal of Medicinal ChemistryISSN
0022-2623External DOI
Issue
2Volume
54Page range
580-590Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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