Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development

被引：295

作者：

Vu, Binh ^{[1
]}

Wovkulich, Peter ^{[1
]}

Pizzolato, Giacomo ^{[1
]}

Lovey, Allen ^{[1
]}

Ding, Qingjie ^{[1
]}

Jiang, Nan ^{[1
]}

Liu, Jin-Jun ^{[1
]}

Zhao, Chunlin ^{[1
]}

Glenn, Kelli ^{[4
]}

Wen, Yang ^{[3
]}

Tovar, Christian ^{[2
]}

Packman, Kathryn ^{[2
]}

Vassilev, Lyubomir ^{[2
]}

Graves, Bradford ^{[3
]}

机构：

[1] Hoffmann La Roche Inc, Roche Res Ctr, Discovery Chem, Nutley, NJ 07110 USA

[2] Hoffmann La Roche Inc, Discovery Oncol, Roche Res Ctr, Nutley, NJ 07110 USA

[3] Hoffmann La Roche Inc, Discovery Technol, Roche Res Ctr, Nutley, NJ 07110 USA

[4] Hoffmann La Roche Inc, Nonclin Dev, Roche Res Ctr, Nutley, NJ 07110 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 05期

关键词：

MDM2; p53; RG7112; protein-protein interaction; cancer; STRUCTURE-BASED DESIGN; P53; PATHWAY; ANTAGONISTS; CANCER; TRANSACTIVATION; ONCOPROTEIN; STABILITY; THERAPY;

D O I：

10.1021/ml4000657

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.

引用

页码：466 / 469

页数：4

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