Portal de Periódicos da CAPES

Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

2014; Elsevier BV; Volume: 22; Issue: 15 Linguagem: Inglês

10.1016/j.bmc.2014.05.072

1464-3391

Zhuming Zhang, Qingjie Ding, Jinjun Liu, Jing Zhang, Nan Jiang, Xin‐Jie Chu, David Bartkovitz, Kin‐Chun Luk, Cheryl A. Janson, Christian Tovar, Zoran Filipovic, Brian Higgins, Kelli Glenn, Kathryn Packman, Lyubomir T. Vassilev, Bradford Graves,

Ubiquitin and proteasome pathways

The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.