Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2011-04, Vol.54 (7), p.2320-2330

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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.