Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer

J Med Chem. 2014 Aug 14;57(15):6332-41. doi: 10.1021/jm500627s. Epub 2014 Jul 9.

Abstract

We recently reported the discovery of AMG 232 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 protein-protein interaction. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer. This article provides an overview of its discovery from the de novo design of the piperidinone series to the structure-activity studies leading to the identification of 1. In addition, this article also describes the preclinical pharmacology and pharmacokinetics of 1, along with its drug metabolism and safety assessment.

Publication types

  • Review

MeSH terms

  • Acetates / adverse effects
  • Acetates / chemistry*
  • Acetates / pharmacology
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Humans
  • Models, Molecular
  • Piperidones / adverse effects
  • Piperidones / chemistry*
  • Piperidones / pharmacology
  • Protein Binding
  • Protein Conformation
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
  • Acetates
  • Antineoplastic Agents
  • Piperidones
  • Proto-Oncogene Proteins c-mdm2