Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
2011; American Chemical Society; Volume: 54; Issue: 7 Linguagem: Inglês
10.1021/jm101488z
ISSN1520-4804
AutoresJean‐Damien Charrier, Steven J. Durrant, Julian M.C. Golec, David P. Kay, Ronald M. A. Knegtel, Somhairle MacCormick, Michael Mortimore, Mike O’Donnell, Joanne L. Pinder, Philip M. Reaper, Alistair P. Rutherford, Paul S. H. Wang, Stephen Young, John R. Pollard,
Tópico(s)Cancer-related Molecular Pathways
ResumoDNA-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 IC(50) 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.
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