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

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journal contribution
posted on 2013-07-25, 00:00 authored by Qingjie Ding, Zhuming Zhang, Jin-Jun Liu, Nan Jiang, Jing Zhang, Tina M. Ross, Xin-Jie Chu, David Bartkovitz, Frank Podlaski, Cheryl Janson, Christian Tovar, Zoran M. Filipovic, Brian Higgins, Kelli Glenn, Kathryn Packman, Lyubomir T. Vassilev, Bradford Graves
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.