SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization

Ismail, Ismail Hassan; Mårtensson, Susanne; Moshinsky, Deborah; Rice, Audie; Tang, Cho; Howlett, Anthony R.; McMahon, Gerald; Hammarsten, Ola

doi:10.1038/sj.onc.1207303

Cited by 75 publications

(48 citation statements)

References 61 publications

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“…The three structurally related PI-3 kinases are responsible for the phosphorylation of g-H2A.X in response to DNA damage, and this phopshorylation can be inhibited by small molecule inhibitors such as wortmannin [Burma et al, 2001;Ismail et al, 2003;Wang et al, 2005]. Interestingly, these large g-H2A.X foci are not sensitive to wortmannin or ATM-specific inhibitors (unpublished data).…”

Section: Functions Of C-h2ax Other Than Dsb Repairmentioning

confidence: 96%

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

Ismail

Hendzel

2007

Environ and Mol Mutagen

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In recent years, several histone modifications have been implicated in the cellular response to DNA double-strand breaks (DSBs). One of the best characterized histone modifications important in DSB repair is the phosphorylation of histone H2A variant, H2A.X. In response to DSBs, H2A.X is phosphorylated and this phosphorylation is required for DSB signaling and the retention of repair proteins at the break site. Despite the existing picture that the function of H2A.X is to promote DNA repair, very recent data suggest that the phosphorylation of histone H2A.X has additional functions. This is analogous to histone H3 phosphorylation on serine 10, which participates in seemingly incompatible functions-transcriptional activation and mitosis. In this review, we discuss the role of histone H2A.X in maintaining genomic stability and review emerging evidence that histone H2A.X is multifunctional. Environ. Mol. Mutagen. 49:73-82, 2008. V V C 2007 Wiley-Liss, Inc.

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Section: Functions Of C-h2ax Other Than Dsb Repairmentioning

confidence: 96%

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

Ismail

Hendzel

2007

Environ and Mol Mutagen

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“…Responses to the combination of DNA-PK inhibitors with DNA-damaging agents include reduced clonogenic survival and cellular proliferation, increased DSBs, G2 arrest and subtle increases in the sub-G1 population (indicative of apoptosis) (Willmore et al, 2004(Willmore et al, , 2008Shinohara et al, 2005), regardless of p53 status (Ismail et al, 2004;Zhao et al, 2006). Recently, Shang et al…”

Section: Arrest/senescencementioning

confidence: 99%

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

et al. 2010

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“…NU7441 shows an excellent selectivity profile across the PIKKs and unrelated kinases and acts as a chemopotentiator both in vitro and in vivo (Zhao et al, 2006). Ismail et al (2004) reported on the identification of SU11752, from a 3-substituted indolin-2-one library, as a 130 nM ATP competitive inhibitor with radiosensitizing properties. This agent abrogates DNA DSB repair without modulating the cell cycle and does not significantly affect ATM function or phosphoinositide-3 kinaseg activity.…”

Section: Inhibitors Of Dna-pkmentioning

confidence: 99%

Targeted cancer therapies based on the inhibition of DNA strand break repair

2007

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Both DNA double-and single-strand break repair are highly coordinated processes utilizing signal transduction cascades and post-translational modifications such as phosphorylation, acetylation and ADP ribosylation. 'Drugable' targets within these networks have been identified that could potentially lead to novel therapeutic approaches within the oncology arena. Key regulators within these signalling cascades, such as DNA-dependent protein kinase, ataxia-telangiectasia mutated, checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2) and poly(ADPribose) polymerase, use either ATP or nicotinamide adenine dinucleotide for their enzymatic functions and are therefore readily accessible to small molecule inhibition at their catalytic sites. A range of highly potent and selective inhibitors of these DNA damage response pathways has now been identified through drug discovery efforts, with candidate molecules either approaching or already in clinical trials. This review will describe the small molecule inhibitors and drug discovery activities that focus on DNA break repair, along with the therapeutic rationale behind chemosensitization and the concept of synthetic lethality. We will also describe the emerging clinical data coming from this exciting new approach to targeted cancer therapy.

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SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization

Cited by 75 publications

References 61 publications

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

Targeted cancer therapies based on the inhibition of DNA strand break repair

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