Identification of a Highly Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor (NU7441) by Screening of Chromenone Libraries.

  title={Identification of a Highly Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor (NU7441) by Screening of Chromenone Libraries.},
  author={Justin J. J. Leahy and Bernard T Golding and Roger John Griffin and Ian R Hardcastle and Caroline J. Richardson and Laurent Jean Martin Rigoreau and Graeme C M Smith},
Activation of DSB processing requires phosphorylation of CtIP by ATR.
It is shown that CtIP undergoes ATR-dependent hyperphosphorylation in response to DSBs, which supports a model in which ATM activity is required for an early step in resection, leading to ATR activation, CtIP-T818 phosphorylation, and accumulation of CtIP on chromatin. Expand
Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes.
A DNA-PKcs-dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM is revealed, which is required for normal levels of p 53 phosphorylation in B and T cells and p53-dependent apoptosis. Expand
DNA-PKcs-SIN1 complexation mediates low-dose X-ray irradiation (LDI)-induced Akt activation and osteoblast differentiation.
The data suggest that DNA-PKcs-SIN1 complexation-mediated Akt activation (Ser-473 phosphorylation) is required for mouse osteoblast differentiation. Expand
TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2-p53 binding antagonists retain sensitivity to ionizing radiation
It is indicated that MDM2/p53 binding antagonists will select for p53 mutations present in tumours at a low frequency at diagnosis, leading to resistance, but such tumours may nevertheless remain responsive to alternative therapies, including IR. Expand
AIM2 controls microglial inflammation to prevent experimental autoimmune encephalomyelitis
In this study, Ma et al. demonstrate that AIM2 negatively regulates the DNA-PK–AKT3 in microglia to control neuroinflammation synergistically induced by cGAS and DNA-PK, thereby preventing theExpand
Comprehensive optimization of a reporter assay toolbox for three distinct CRISPR‐Cas systems
A series of reporter assays to probe mechanisms of action of various editing processes, including nonhomologous DNA end joining, homology‐directed repair and single‐strand annealing are developed. Expand
Customization and improvement of the LbCas12a-crRNA system for efficient gene targeting in plants
The significance of the selection of gene scissors, the appropriate design of LbCas12a gRNAs, the use of chemical treatments, and the establishment of favorable experimental conditions for further enhancement of plant HDR to enable efficient GT in tomato are demonstrated. Expand
Dual targeting of higher-order DNA structures by azacryptands induces DNA junction-mediated DNA damage in cancer cells
It is shown here that cytotoxic activity of TWJ-/G4-ligands is mitigated by the DNA damage response (DDR) and DNA topoisomerase 2 (TOP2), making them different from typical G4- ligands, and implying a pivotal role of TWJs in cells. Expand


Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries.
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 repairExpand