title: Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer.
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.
authors: Department of Therapeutic Discovery, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors: Yosup
authors: Y
authors: Rew
authors: Daqing
authors: D
authors: Sun
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D010881:Piperidones / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C588087:2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; D000085:Acetates; D000970:Antineoplastic Agents; D010881:Piperidones; D051736:Proto-Oncogene Proteins c-mdm2