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Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold.

Abstract
From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 microM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC(50) = 5.3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.
AuthorsIan R Hardcastle, Shafiq U Ahmed, Helen Atkins, 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
JournalJournal of medicinal chemistry (J Med Chem) Vol. 49 Issue 21 Pg. 6209-21 (Oct 19 2006) ISSN: 0022-2623 [Print] United States
PMID17034127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one
  • 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one
  • Antineoplastic Agents
  • Indoles
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Combinatorial Chemistry Techniques
  • Drug Screening Assays, Antitumor
  • Humans
  • Indoles (chemical synthesis, chemistry, pharmacology)
  • Models, Molecular
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 (metabolism)
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 (genetics, metabolism)

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