Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs.
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We thank A. Peek, S. Falcon, M. Mangan, H. Sundaram and P. Weber for support with cell screening studies; P. Wang and J. Westcott for support with biochemical studies; R. Long for help generating the final figures and the full ATR project team for efforts leading to VE-821.
All authors are full time employees of Vertex Pharmaceuticals (Europe), Ltd. and hold equity in Vertex Pharmaceuticals, Inc.
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Reaper, P., Griffiths, M., Long, J. et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7, 428–430 (2011). https://doi.org/10.1038/nchembio.573
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