Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents

被引：191

作者：

Charrier, Jean-Damien ^{[2
]}

Durrant, Steven J. ^{[2
]}

Golec, Julian M. C. ^{[2
]}

Kay, David P. ^{[2
]}

Knegtel, Ronald M. A. ^{[2
]}

MacCormick, Somhairle ^{[2
]}

Mortimore, Michael ^{[2
]}

O'Donnell, Michael E. ^{[2
]}

Pinder, Joanne L. ^{[2
]}

Reaper, Philip M. ^{[1
]}

Rutherford, Alistair P. ^{[2
]}

Wang, Paul S. H. ^{[1
]}

Young, Stephen C. ^{[2
]}

Pollard, John R. ^{[1
]}

机构：

[1] Vertex Pharmaceut Europe Ltd, Dept Biol, Abingdon OX14 4RY, Oxon, England

[2] Vertex Pharmaceut Europe Ltd, Dept Chem, Abingdon OX14 4RY, Oxon, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 07期

关键词：

CANCER; CELLS; PROGRESSION; ACTIVATION; CARCINOMA; DESIGN; REPAIR; MODEL; P53;

D O I：

10.1021/jm101488z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 K-i 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 mu 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.

引用

页码：2320 / 2330

页数：11

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