4QO4

co-crystal structure of MDM2 (17-111) with compound 16, {(3R,5R,6S)-5-(3-CHLOROPHENYL)-6-(4-CHLOROPHENYL)-1-[(1S)-1-(6-CYCLOPROPYLPYRIDIN-2-YL)PROPYL]-3-METHYL-2-OXOPIPERIDIN-3-YL}ACETIC ACID

Summary for 4QO4

• Entry DOI: 10.2210/pdb4qo4/pdb
• Related: 4QOC
• Descriptor: E3 ubiquitin-protein ligase Mdm2, {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-(6-cyclopropylpyridin-2-yl)propyl]-3-methyl-2-oxopiperidin-3-yl}acetic acid (3 entities in total)
• Functional Keywords: mdm2, p53, protein-protein interaction, inhibitor, 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: 11707.56

Authors

Huang, X. (deposition date: 2014-06-19, release date: 2014-07-16, Last modification date: 2024-02-28)

Primary citation

Yu, M.,Wang, Y.,Zhu, J.,Bartberger, M.D.,Canon, J.,Chen, A.,Chow, D.,Eksterowicz, J.,Fox, B.,Fu, J.,Gribble, M.,Huang, X.,Li, Z.,Liu, J.J.,Lo, M.C.,McMinn, D.,Oliner, J.D.,Osgood, T.,Rew, Y.,Saiki, A.Y.,Shaffer, P.,Yan, X.,Ye, Q.,Yu, D.,Zhao, X.,Zhou, J.,Olson, S.H.,Medina, J.C.,Sun, D.
Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.
ACS Med Chem Lett, 5:894-899, 2014

PubMed Abstract: Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.

PubMed: 25147610
DOI: 10.1021/ml500142b

Experimental method

X-RAY DIFFRACTION (1.7 Å)