Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction

  • Bioorg Med Chem Lett. 2005 Mar 1;15(5):1515-20. doi: 10.1016/j.bmcl.2004.12.061.
Ian R Hardcastle  1 ,  Shafiq U Ahmed ,  Helen Atkins ,  A Hilary Calvert ,  Nicola J Curtin ,  Gillian Farnie ,  Bernard T Golding ,  Roger J Griffin ,  Sabrina Guyenne ,  Claire Hutton ,  Per Källblad ,  Stuart J Kemp ,  Martin S Kitching ,  David R Newell ,  Stefano Norbedo ,  Julian S Northen ,  Rebecca J Reid ,  K Saravanan ,  Henriëtte M G Willems ,  John Lunec
Affiliations
  • 1. Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK. [email protected]
PMID: 15713419 DOI: 10.1016/j.bmcl.2004.12.061
Abstract

A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 microM in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line.