4WT2

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

4WT2 の概要

• エントリーDOI: 10.2210/pdb4wt2/pdb
• 分子名称: 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)
• 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: 12984.90

構造登録者

Shaffer, P.L.,Huang, X.,Yakowec, P.,Long, A.M. (登録日: 2014-10-30, 公開日: 2014-12-03, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.42 Å)