4JVE

Co-crystal structure of MDM2 with inhibitor (2R,3E)-2-[(2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholin-4-yl]pent-3-enoic acid

4JVE の概要

• エントリーDOI: 10.2210/pdb4jve/pdb
• 関連するPDBエントリー: 4JV7 4JV9 4JVR 4JWR
• 分子名称: E3 ubiquitin-protein ligase Mdm2, (2R,3E)-2-[(2S,3R,6S)-2,3-bis(4-chlorophenyl)-6-(4-fluorobenzyl)-5-oxomorpholin-4-yl]pent-3-enoic acid (3 entities in total)
• 機能のキーワード: p53, protein-protein interaction, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11684.45

構造登録者

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. (登録日: 2013-03-25, 公開日: 2013-05-01, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)