36204-92-9Relevant articles and documents
INHIBITING ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN (ATR)
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Paragraph 0028; 0029; 0030, (2017/08/08)
Novel compounds inhibiting ATR protein kinase include compounds of formula (I) disclosed herein, as well as liposome formulations comprising ATR protein kinase inhibitor compounds. The compositions are useful for the treatment of cancer.
Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
Charrier, Jean-Damien,Durrant, Steven J.,Golec, Julian M. C.,Kay, David P.,Knegtel, Ronald M. A.,MacCormick, Somhairle,Mortimore, Michael,O'Donnell, Michael E.,Pinder, Joanne L.,Reaper, Philip M.,Rutherford, Alistair P.,Wang, Paul S. H.,Young, Stephen C.,Pollard, John R.
, p. 2320 - 2330 (2011/06/17)
DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a Ki of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC50 of 0.42 μM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.