4ERF

crystal structure of MDM2 (17-111) in complex with compound 29 (AM-8553)

Summary for 4ERF

• Entry DOI: 10.2210/pdb4erf/pdb
• Related: 4ERE
• Descriptor: E3 ubiquitin-protein ligase Mdm2, {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S,3S)-2-hydroxypentan-3-yl]-3-methyl-2-oxopiperidin-3-yl}acetic acid (3 entities in total)
• Functional Keywords: mdm2, p53, protein protein interaction, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 3
• Total formula weight: 34903.38

Authors

Huang, X. (deposition date: 2012-04-20, release date: 2012-05-23, Last modification date: 2024-02-28)

Primary citation

Rew, Y.,Sun, D.,Gonzalez-Lopez De Turiso, F.,Bartberger, M.D.,Beck, H.P.,Canon, J.,Chen, A.,Chow, D.,Deignan, J.,Fox, B.M.,Gustin, D.,Huang, X.,Jiang, M.,Jiao, X.,Jin, L.,Kayser, F.,Kopecky, D.J.,Li, Y.,Lo, M.C.,Long, A.M.,Michelsen, K.,Oliner, J.D.,Osgood, T.,Ragains, M.,Saiki, A.Y.,Schneider, S.,Toteva, M.,Yakowec, P.,Yan, X.,Ye, Q.,Yu, D.,Zhao, X.,Zhou, J.,Medina, J.C.,Olson, S.H.
Structure-based design of novel inhibitors of the MDM2-p53 interaction.
J.Med.Chem., 55:4936-4954, 2012

PubMed Abstract: 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.

PubMed: 22524527
DOI: 10.1021/jm300354j

Experimental method

X-RAY DIFFRACTION (2 Å)