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

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

Affiliation

  • 1 Chemistry Department, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, United Kingdom.
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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