4JV7

Co-crystal structure of MDM2 with inhibitor (2S,5R,6S)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one

Summary for 4JV7

• Entry DOI: 10.2210/pdb4jv7/pdb
• Related: 4JV9 4JVE 4JVR 4JWR
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (2S,5R,6S)-2-benzyl-5,6-bis(4-bromophenyl)-4-methylmorpholin-3-one, 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: 11767.35

Authors

Huang, X.,Gonzalez-Lopez de Turiso, F.,Sun, D.,Yosup, R.,Bartberger, M.D.,Beck, H.P.,Cannon, J.,Shaffer, P.,Oliner, J.D.,Olson, S.H.,Medina, J.C. (deposition date: 2013-03-25, release date: 2013-05-01, Last modification date: 2024-02-28)

Primary citation

Gonzalez-Lopez de Turiso, F.,Sun, D.,Rew, Y.,Bartberger, M.D.,Beck, H.P.,Canon, J.,Chen, A.,Chow, D.,Correll, T.L.,Huang, X.,Julian, L.D.,Kayser, F.,Lo, M.C.,Long, A.M.,McMinn, D.,Oliner, J.D.,Osgood, T.,Powers, J.P.,Saiki, A.Y.,Schneider, S.,Shaffer, P.,Xiao, S.H.,Yakowec, P.,Yan, X.,Ye, Q.,Yu, D.,Zhao, X.,Zhou, J.,Medina, J.C.,Olson, S.H.
Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.
J.Med.Chem., 56:4053-4070, 2013

PubMed Abstract: Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.

PubMed: 23597064
DOI: 10.1021/jm400293z

Experimental method

X-RAY DIFFRACTION (2.2 Å)