Discovery of a Small Molecule MDM2 Inhibitor (AMG 232) for Treating Cancer

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 n...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 57; no. 15; pp. 6332 - 6341
Main Authors Rew, Yosup, Sun, Daqing
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 14.08.2014
Subjects
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
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Summary: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.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-3
content type line 23
ObjectType-Review-1
ISSN:0022-2623
1520-4804
DOI:10.1021/jm500627s