Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
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- 作者：Jean-Damien Charrier ; Steven J. Durrant ; Julian M. C. Golec ; David P. Kay ; Ronald M. A. Knegtel ; Somhairle MacCormick ; Michael Mortimore ; Michael E. O'Donnell ; Joanne L. Pinder ; Philip M. Reaper ; Alistair P. Rutherford ; Paul S. H. Wang ; Stephen C. Young ; John R. Pollard
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：April 14, 2011
- 年：2011
- 卷：54
- 期：7
- 页码：2320-2330
- 全文大小：1041K
- 年卷期：v.54,no.7(April 14, 2011)
- ISSN：1520-4804
文摘
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 渭M. 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.