Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development

被引：495

作者：

Ding, Qingjie ^{[1
]}

Zhang, Zhuming ^{[1
]}

Liu, Jin-Jun ^{[1
]}

Jiang, Nan ^{[1
]}

Zhang, Jing ^{[1
]}

Ross, Tina M. ^{[1
]}

Chu, Xin-Jie ^{[1
]}

Bartkovitz, David ^{[1
]}

Podlaski, Frank ^{[2
]}

Janson, Cheryl ^{[2
]}

Tovar, Christian ^{[3
]}

Filipovic, Zoran M. ^{[3
]}

Higgins, Brian ^{[3
]}

Glenn, Kelli ^{[4
]}

Packman, Kathryn ^{[3
]}

Vassilev, Lyubomir T. ^{[3
]}

Graves, Bradford ^{[2
]}

机构：

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

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

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 14期

关键词：

ASYMMETRIC 1,3-DIPOLAR CYCLOADDITION; P53; PATHWAY; AZOMETHINE YLIDES; ANTAGONIST RG7112; MDM2; INHIBITORS; PROLINE; CANCER; RING;

D O I：

10.1021/jm400487c

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

引用

页码：5979 / 5983

页数：5

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