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First published on July 6, 2007; DOI: 10.1124/mol.107.035832

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Received for publication March 8, 2007.
Revised July 5, 2007.
Accepted for publication July 6, 2007.

Identification of a bis-guanylhydrazone (NSC 109555) as a novel chemotype for inhibition of Chk2 kinase

Andrew G Jobson 1, John H Cardellina II 1, Dominic Scudiero 1, Sudhir Kondapaka 1, Hongliang Zhang 1, Hijoo Kim 1, Robert Shoemaker 1, Yves G. Pommier 1*

1 NIH

* Address correspondence to: E-mail: pommier{at}nih.gov

Abstract

Chk2 is a protein kinase involved in the ATM-dependent checkpoint pathway (http://discover.nci.nih.gov/mim). This pathway is activated by genomic instability and DNA damage and results in either cell cycle arrest to allow DNA repair to occur, or cell death (apoptosis). Chk2 is activated by ATM-mediated phosphorylation and autophosphorylation, and in turn phosphorylates its downstream targets (Cdc25A, Cdc25C, BRCA1, p53, Hdmx, E2F1, PP2A and PML). Inhibition of Chk2 has been proposed to sensitize p53-deficient cells, as well as protect normal tissue following exposure to DNA-damaging agents. We have developed a drug-screening program for specific Chk2 inhibitors using a fluorescence polarization assay, IMAP. This assay detects the degree of phosphorylation of a fluorescently-linked substrate by Chk2. From a screen of over 100,000 compounds from the NCI Developmental Therapeutics Program (DTP), we identified a bis-guanylhydrazone (NSC 109555) as a lead compound. In vitro data show the specific inhibition of Chk2 kinase activity by NSC 109555 using in vitro kinase assays and kinase-profiling experiments. NSC 109555 was shown to be a competitive inhibitor of Chk2 with respect to ATP, which was supported by docking of NSC 109555 into the ATP binding pocket of the Chk2 catalytic domain. The potency of NSC 109555 was comparable to other known Chk2 inhibitors, DBH (debromohymenialdisine) and 2-arylbenzimidazole. These data define a novel chemotype for the development of potent and selective inhibitors of Chk2. Ultimately this class of drugs may be useful in combination with current DNA-damaging agents used in the clinic.


Key words: Apoptosis, DNA damage and repair, Tumor suppressors


This article has been cited by other articles:


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Chk1 and Chk2 are differentially involved in homologous recombination repair and cell cycle arrest in response to DNA double-strand breaks induced by camptothecins
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[Abstract] [Full Text] [PDF]


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