4QOC

crystal structure of compound 16 bound to MDM2(17-111), {(3R,5R,6S)-5-(3-CHLOROPHENYL)-6-(4-CHLOROPHENYL)-1-[(1S)-1-CYCLOPROPYL-2-(PYRROLIDIN-1-YLSULFONYL)ETHYL]-3-METHYL-2-OXOPIPERIDIN-3-YL}ACETIC ACID

4QOC の概要

• エントリーDOI: 10.2210/pdb4qoc/pdb
• 関連するPDBエントリー: 4QO4
• 分子名称: E3 ubiquitin-protein ligase Mdm2, {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-(pyrrolidin-1-ylsulfonyl)ethyl]-3-methyl-2-oxopiperidin-3-yl}acetic acid (3 entities in total)
• 機能のキーワード: mdm2, p53, protein-protein interaction, inhibitor, 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: 6
• 化学式量合計: 70497.68

構造登録者

Huang, X. (登録日: 2014-06-19, 公開日: 2015-05-06, 最終更新日: 2024-02-28)

主引用文献

Wang, Y.,Zhu, J.,Liu, J.J.,Chen, X.,Mihalic, J.,Deignan, J.,Yu, M.,Sun, D.,Kayser, F.,McGee, L.R.,Lo, M.C.,Chen, A.,Zhou, J.,Ye, Q.,Huang, X.,Long, A.M.,Yakowec, P.,Oliner, J.D.,Olson, S.H.,Medina, J.C.
Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.
Bioorg.Med.Chem.Lett., 24:3782-3785, 2014

PubMed Abstract: We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.

PubMed: 25042256
DOI: 10.1016/j.bmcl.2014.06.073

実験手法

X-RAY DIFFRACTION (1.7 Å)