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

Caldwell, John J., Welsh, Emma J., Matijssen, Cornelis, Anderson, Victoria E., Antoni, Laurent, Boxall, Kathy, Urban, Frederique, Hayes, Angela, Raynaud, Florence I., Rigoreau, Laurent J. M., and others. (2010) 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. (doi:10.1021/jm101150b) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://doi.org/10.1021/jm101150b

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). Structure?activity 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
DOI/Identification number: 10.1021/jm101150b
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 Nov 2016 11:11 UTC
Last Modified: 29 May 2019 18:11 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/58571 (The current URI for this page, for reference purposes)
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