Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development
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- 作者：Binh Vu ; Peter Wovkulich ; Giacomo Pizzolato ; Allen Lovey ; Qingjie Ding ; Nan Jiang ; Jin-Jun Liu ; Chunlin Zhao ; Kelli Glenn ; Yang Wen ; Christian Tovar ; Kathryn Packman ; Lyubomir Vassilev ; Bradford Graves
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：May 9, 2013
- 年：2013
- 卷：4
- 期：5
- 页码：466-469
- 全文大小：272K
- 年卷期：v.4,no.5(May 9, 2013)
- ISSN：1948-5875
文摘
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.