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

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.
Mesh Terms:
Acetates, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Hepatocytes, Humans, Macaca fascicularis, Mice, Mice, Nude, Models, Molecular, Molecular Conformation, Neoplasm Transplantation, Piperidones, Protein Binding, Proto-Oncogene Proteins c-mdm2, Rats, Stereoisomerism, Structure-Activity Relationship, Transplantation, Heterologous, Tumor Suppressor Protein p53, rho GTP-Binding Proteins
J. Med. Chem.
Date: Jun. 14, 2012
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