2026-07-21T21:54:55Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/176842024-11-29T17:40:08Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Toledo, Luis I author Murga, Matilde author Zur, Rafal author Soria, Rebeca author Rodriguez, Antonio author Martinez, Sonia author Oyarzabal, Julen author Pastor, Joaquin author Bischoff, James R author Fernandez-Capetillo, Oscar author 2011-06 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). Nat Struct Mol Biol . 2011;18(6):721-7 10.1038/nsmb.2076 1545-9985 Nature structural & molecular biology https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869831/ 21552262 http://hdl.handle.net/20.500.12105/17684 A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.