4WT2

Co-crystal Structure of MDM2 in Complex with AM-7209

Summary for 4WT2

• Entry DOI: 10.2210/pdb4wt2/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 4-({[(3R,5R,6S)-1-[(1S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl]-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetyl}amino)-2-methoxybenzoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: 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: 1
• Total formula weight: 12984.90

Authors

Shaffer, P.L.,Huang, X.,Yakowec, P.,Long, A.M. (deposition date: 2014-10-30, release date: 2014-12-03, Last modification date: 2023-09-27)

Primary citation

Rew, Y.,Sun, D.,Yan, X.,Beck, H.P.,Canon, J.,Chen, A.,Duquette, J.,Eksterowicz, J.,Fox, B.M.,Fu, J.,Gonzalez, A.Z.,Houze, J.,Huang, X.,Jiang, M.,Jin, L.,Li, Y.,Li, Z.,Ling, Y.,Lo, M.C.,Long, A.M.,McGee, L.R.,McIntosh, J.,Oliner, J.D.,Osgood, T.,Saiki, A.Y.,Shaffer, P.,Wang, Y.C.,Wortman, S.,Yakowec, P.,Ye, Q.,Yu, D.,Zhao, X.,Zhou, J.,Medina, J.C.,Olson, S.H.
Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.
J.Med.Chem., 57:10499-10511, 2014

PubMed Abstract: Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

PubMed: 25384157
DOI: 10.1021/jm501550p

Experimental method

X-RAY DIFFRACTION (1.42 Å)