2. Academic Validation
  3. Structure-based design of novel inhibitors of the MDM2-p53 interaction

Structure-based design of novel inhibitors of the MDM2-p53 interaction

  • J Med Chem. 2012 Jun 14;55(11):4936-54. doi: 10.1021/jm300354j.
Yosup Rew 1,  Daqing Sun,  Felix Gonzalez-Lopez De Turiso,  Michael D Bartberger,  Hilary P Beck,  Jude Canon,  Ada Chen,  David Chow,  Jeffrey Deignan,  Brian M Fox,  Darin Gustin,  Xin Huang,  Min Jiang,  Xianyun Jiao,  Lixia Jin,  Frank Kayser,  David J Kopecky,  Yihong Li,  Mei-Chu Lo,  Alexander M Long,  Klaus Michelsen,  Jonathan D Oliner,  Tao Osgood,  Mark Ragains,  Anne Y Saiki,  Steve Schneider,  Maria Toteva,  Peter Yakowec,  Xuelei Yan,  Qiuping Ye,  Dongyin Yu,  Xiaoning Zhao,  Jing Zhou,  Julio C Medina,  Steven H Olson
Affiliations

Affiliation

  • 1 Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 22524527 DOI: 10.1021/jm300354j
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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