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

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 prot...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2013-05, Vol.4 (5), p.466-469
Main Authors: Vu, Binh, Wovkulich, Peter, Pizzolato, Giacomo, Lovey, Allen, Ding, Qingjie, Jiang, Nan, Liu, Jin-Jun, Zhao, Chunlin, Glenn, Kelli, Wen, Yang, Tovar, Christian, Packman, Kathryn, Vassilev, Lyubomir, Graves, Bradford
Format: Article
Language:English
Subjects:
Letter
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml4000657