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 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.