Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/17684
Título
A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.
Autor(es)
Fecha de publicación
2011-06
Cita
Nat Struct Mol Biol . 2011;18(6):721-7
Idioma
Inglés
Tipo de documento
journal article
Resumen
Oncogene activation has been shown to generate replication-born DNA damage, also known as replicative stress. The primary responder to replicative stress is not Ataxia-Telangiectasia Mutated (ATM) but rather the kinase ATM and Rad3-related (ATR). One limitation for the study of ATR is the lack of potent inhibitors. We here describe a cell-based screening strategy that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range. Pharmacological inhibition of ATR generates replicative stress, leading to chromosomal breakage in the presence of conditions that stall replication forks. Moreover, ATR inhibition is particularly toxic for p53-deficient cells, this toxicity being exacerbated by replicative stress-generating conditions such as the overexpression of cyclin E. Notably, one of the compounds we identified is NVP-BEZ235, a dual phosphatidylinositol-3-OH kinase (PI3K) and mTOR inhibitor that is being tested for cancer chemotherapy but that we now show is also very potent against ATM, ATR and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).
MESH
Animals | Antineoplastic Agents | Ataxia Telangiectasia Mutated Proteins | Cell Cycle Proteins | Cell Survival | Cells, Cultured | Chromosome Breakage | Drug Screening Assays, Antitumor | Enzyme Inhibitors | Fibroblasts | Imidazoles | Mice | Oxazines | Protein Serine-Threonine Kinases | Quinolines | Tumor Suppressor Protein p53
Versión en línea
DOI
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