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

作者：Ding, Qingjie; Zhang, Zhuming^*; Liu, Jin-Jun; Jiang, Nan; Zhang, Jing; Ross, Tina M.; Chu, Xin-Jie; Bartkovitz, David; Podlaski, Frank; Janson, Cheryl; Tovar, Christian; Filipovic, Zoran M.; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir T.; Graves, Bradford

来源：Journal of Medicinal Chemistry, 2013, 56(14): 5979-5983.

DOI：10.1021/jm400487c

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

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.

• 出版日期2013-7-25