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

被引：131

作者：

Hardcastle, Ian R.

Ahmed, Shafiq U.

Atkins, Helen

Farnie, Gillian

Golding, Bernard T.

Griffin, Roger J.

Guyenne, Sabrina

Hutton, Claire

Kallblad, Per

Kemp, Stuart J.

Kitching, Martin S.

Newell, David R.

Norbedo, Stefano

Northen, Julian S.

Reid, Rebecca J.

Saravanan, K.

Willems, Henriette M. G.

Lunec, John

机构：

[1] Univ Newcastle Upon Tyne, No Inst Canc Res, Sch Nat Sci Chem, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[2] Univ Newcastle Upon Tyne, Sch Med, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[3] De Novo Pharmaceut, Cambridge CB4 9ZR, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 21期

关键词：

D O I：

10.1021/jm0601194

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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; IC50 = 15.9 +/- 0.8 mu M) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC50) 5.3 (0.9 mu M), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.

引用

页码：6209 / 6221

页数：13

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