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

作者：Qingjie Ding, Zhuming Zhang, Jinjun Liu, Nan Jiang, Jing Zhang, Tina Morgan Ross, Xin‐Jie Chu, David Bartkovitz, Frank Podlaski, Cheryl A. Janson, Christian Tovar, Zoran Filipovic, Brian Higgins, Kelli Glenn, Kathryn E. Packman, Lyubomir T. Vassilev, Bradford J. Graves · 发表于：Journal of Medicinal Chemistry · 年份：2013 · DOI：10.1021/jm400487c · 被引用次数：610 · 研究领域：Cancer-related Molecular Pathways、Microtubule and mitosis dynamics、Ubiquitin and proteasome pathways

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.