Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents - PubMed (original) (raw)

. 2011 Apr 14;54(7):2320-30.

doi: 10.1021/jm101488z. Epub 2011 Mar 17.

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

Affiliations

Jean-Damien Charrier et al. J Med Chem. 2011.

Abstract

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 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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