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

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.

• Authors: Ian R Hardcastle, 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
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 15 Issue 5 Pg. 1515-20 (Mar 01 2005) ISSN: 0960-894X [Print] England
• PMID: 15713419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one
• Indoles
• Nuclear Proteins
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Nuclear Proteins (chemistry, drug effects, metabolism)
• Protein Binding (drug effects)
• Proto-Oncogene Proteins (chemistry, drug effects, metabolism)
• Proto-Oncogene Proteins c-mdm2
• Structure-Activity Relationship
• Transcription, Genetic (drug effects)
• Tumor Suppressor Protein p53 (chemistry, drug effects, genetics, metabolism)