The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index.
Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM
Open accessAbstract
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, gammaH2AX, 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.
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“The translocation of USP10 could be blocked by the ATM inhibitor Ku55933”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Hickson et al., 2004
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Cites
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
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ATM and related protein kinases: safeguarding genome integrity
Shiloh, Y. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1011 · Cited by 2,577
Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53
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Cell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966
ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks
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Enhanced Phosphorylation of p53 by ATM in Response to DNA Damage
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ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation
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Metadata
- Authors
- Hickson, I., Zhao, Y., Richardson, C. J., Green, S. J., Martin, N. M. B., Orr, A. I., Reaper, P. M., Jackson, S. P., Curtin, N. J., & Smith, G. C. M.
- Affiliations
- 1KuDOS Pharmaceuticals Ltd., Cambridge Science Park, Milton Road, Cambridge;
- Newcastle University (GB)
- University of Cambridge (GB)
- ORCID
- Venue
- Cancer Research
- Published
- 2004-12-15
- Volume
- 64
- Issue
- 24
- Pages
- 9152-9159
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2101988823
- Cited by
- 1,220
- References
- 58
- Citations by year
- 2026: 26 · 2025: 31 · 2024: 38 · 2023: 49 · 2022: 31 · 2021: 32 · 2020: 53 · 2019: 55 · 2018: 48 · 2017: 66 · 2016: 71 · 2015: 76 · 2014: 70 · 2013: 62 · 2012: 92
- FWCI
- 11.39
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- ATM kinase, KU55933, kinase inhibitors, ataxia telangiectasia, radiosensitivity, DNA double-strand breaks, cell cycle arrest, p53 phosphorylation, NBS1, radiosensitization, chemosensitization, etoposide, doxorubicin, camptothecin, γH2AX, SMC1A
- MeSH terms
- Cell Cycle, Chromones, DNA-Binding Proteins, HeLa Cells, Humans, Kinetics, Morpholines, Phosphorylation, Pyrones, Radiation-Sensitizing Agents, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Inhibitory Concentration 50, Combinatorial Chemistry Techniques, Tumor Suppressor Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, Ataxia Telangiectasia Mutated Proteins
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