Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2.

Caldwell, John J, Welsh, Emma J, Matjissen, Cornelis, Anderson, Victoria E, Antoni, Laurent, Boxall, Kathy, Urban, Frederique, Hayes, Angela, Raynaud, Florence I, Rigoreau, Laurent J M, Raynham, Tony, Aherne, G Wynne, Pearl, Laurence H, Oliver, Antony W, Garrett, Michelle D and Collins, Ian (2011) Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2. Journal of Medicinal Chemistry, 54 (2). pp. 580-590. ISSN 0022-2623

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Abstract

Structure-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).

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
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Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 20:44
Last Modified: 30 Nov 2012 17:08
URI: http://sro.sussex.ac.uk/id/eprint/27828
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