Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction Based on an Isoindolinone Scaffold
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- 作者：Ian R. Hardcastle ; Shafiq U. Ahmed ; Helen Atkins ; Gillian Farnie ; Bernard T. Golding ; Roger J. Griffin ; Sabrina Guyenne ; Claire Hutton ; Per Kä ; llblad ; Stuart J. Kemp ; Martin S. Kitching ; David R.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：October 19, 2006
- 年：2006
- 卷：49
- 期：21
- 页码：6209 - 6221
- 全文大小：570K
- 年卷期：v.49,no.21(October 19, 2006)
- ISSN：1520-4804
文摘
From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a seriesof 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; IC50 = 15.9 ± 0.8 
M) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC50 = 5.3 ± 0.9 M), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.
M) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC50 = 5.3 ± 0.9 M), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.