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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage. Expand
Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM
- Ian D. Hickson, Yan Zhao, +7 authors Graeme C M Smith
- Medicine, Biology
- Cancer Research
- 15 December 2004
KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase, which did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage. Expand
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
It is shown that ATM and the nuclease activity of meiotic recombination 11 are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Expand
A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.
It is shown that ataxia telangiectasia mutated protein (ATM) and Artemis, the protein defective in patients with RS-SCID, function in a common double-strand break repair pathway that also requires H2AX, 53BP1, Nbs1, Mre11, and DNA-PK. Expand
AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.
AZD8055 is described, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L, which results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. Expand
Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
The results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness. Expand
Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1.
- S. Veuger, N. Curtin, C. Richardson, Graeme C M Smith, B. Durkacz
- Biology, Medicine
- Cancer research
- 15 September 2003
There was a correlation between the ability of the inhibitors to prevent IR-induced DNA DSB repair and their ability to potentiate cytotoxicity and the DNA-PK and PARP-1 inhibitors show potential as tools for anticancer therapeutic intervention. Expand
Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation
It is demonstrated that yeast artificial chromosomes containing the DNA- PKcs gene complement both the DNA repair and recombination deficiencies of V3 cells, and it is concluded that DNA-PKcs is encoded by the XRCC7 gene. Expand
Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441.
NU7441 shows sufficient proof of principle through in vitro and in vivo chemos Sensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use. Expand
Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries.
- Justin J. J. Leahy, B. Golding, +4 authors Graeme C M Smith
- Chemistry, Medicine
- Bioorganic & medicinal chemistry letters
- 20 December 2004
A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries, which were screened as inhibitors of the DNA repair… Expand