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Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM

Lookup NU author(s): Dr Yan Zhao, Dr Susan Jackson, Professor Nicola Curtin

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Abstract

The serine/threonine protein kinase ATM signals to cell cycle and DNA repair components by phosphorylating downstream targets such as p53, CHK2, NBS1, and BRCA1. Mutation of ATM occurs in the human autosomal recessive disorder ataxia-telangiectasia, which is characterized by hypersensitivity to ionizing radiation and a failure of cells to arrest the cell cycle after the induction of DNA double-strand breaks. It has thus been proposed that ATM inhibition would cause cellular radio- and chemosensitization. Through screening a small molecule compound library developed for the phosphatidylinositol 3′-kinase-like kinase family, we identified an ATP-competitive inhibitor, 2-morpholin-4-yl-6- thianthren-1-yl-pyran-4-one (KU-55933), that inhibits ATM with an IC 50 of 13 nmol/L and a Ki of 2.2 nmol/L. KU-55933 shows specificity with respect to inhibition of other phosphatidylinositol 3′-kinase-like kinases. Cellular inhibition of ATM by KU-55933 was demonstrated by the ablation of ionizing radiation-dependent phosphorylation of a range of ATM targets, including p53, γH2AX, NBS1, and SMC1. KU-55933 did not show inhibition of UV light DNA damage induced cellular phosphorylation events. Exposure of cells to KU-55933 resulted in a significant sensitization to the cytotoxic effects of ionizing radiation and to the DNA double-strand break-inducing chemotherapeutic agents, etoposide, doxorubicin, and camptothecin. Inhibition of ATM by KU-55933 also caused a loss of ionizing radiation-induced cell cycle arrest. By contrast, KU-55933 did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage. We conclude that KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase.


Publication metadata

Author(s): Hickson, I., Zhao, Y., Richardson, C., Green, S., Martin, N., Orr, A., Reaper, P., Jackson, S., Curtin, N.J., Smith, G.

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2004

Volume: 64

Issue: 24

Pages: 9152-9159

Print publication date: 15/12/2004

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

URL: http://dx.doi.org/10.1158/0008-5472.CAN-04-2727

DOI: 10.1158/0008-5472.CAN-04-2727

PubMed id: 15604286


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