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

  • J Med Chem. 2011 Apr 14;54(7):2320-30. doi: 10.1021/jm101488z.
Jean-Damien Charrier  1 ,  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
  • 1. Chemistry Department, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, United Kingdom.
PMID: 21413798 DOI: 10.1021/jm101488z
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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