Structure-Based Design of Novel Inhibitors of the MDM2–p53 Interaction
Yosup Rew, Daqing Sun, Felix González-López de Turiso, Michael D. Bartberger, Hilary P. Beck, Jude Canon, Ada Chen, David Chow, Jeffrey Deignan, Brian M. Fox, Darin J. Gustin, Xin Huang(Amgen (United States)), Min Jiang, Xian‐Yun Jiao, Lixia Jin, Frank Kayser, David J. Kopecky, Yihong Li, Mei-Chu Lo, Alexander Long(Amgen (United States)), Klaus Michelsen, Jonathan D. Oliner, Tao Osgood, Mark L. Ragains, Anne Y. Saiki, Steve Schneider(Amgen (United States)), Maria M. Toteva, P. Yakowec(Amgen (United States)), Xuelei Yan, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Julio C. Medina, Steven H. Olson
Cited by 169Open Access
Abstract
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
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