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CCT241533 Is a Potent and Selective Inhibitor of CHK2 that Potentiates the Cytotoxicity of PARP Inhibitors

Anderson, Victoria E., Walton, Michael I., Eve, Paul D., Boxall, Katherine J., Antoni, Laurent, Caldwell, John J., Aherne, Wynne, Pearl, Laurence H., Oliver, Antony W., Collins, Ian, and others. (2011) CCT241533 Is a Potent and Selective Inhibitor of CHK2 that Potentiates the Cytotoxicity of PARP Inhibitors. Cancer Research, 71 (2). pp. 463-472. ISSN 0008-5472. (doi:10.1158/0008-5472.CAN-10-1252) (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)

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Official URL
http://doi.org/10.1158/0008-5472.CAN-10-1252

Abstract

CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC50 of 3 nmol/L and shows minimal cross-reactivity against a panel of kinases at 1 ?mol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone, and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors.

Item Type: Article
DOI/Identification number: 10.1158/0008-5472.CAN-10-1252
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 Nov 2016 10:57 UTC
Last Modified: 13 Mar 2020 04:08 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/58568 (The current URI for this page, for reference purposes)
Garrett, Michelle D.: https://orcid.org/0000-0002-3939-1673
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