4OGN

Co-Crystal Structure of MDM2 with Inhbitor Compound 3

4OGN の概要

• エントリーDOI: 10.2210/pdb4ogn/pdb
• 分子名称: E3 ubiquitin-protein ligase Mdm2, 6-{[(3R,5R,6S)-1-[(1S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl}pyridine-3-carboxylic 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: 12894.85

構造登録者

Shaffer, P.L.,Huang, X.,Yakowec, P.,Long, A.M. (登録日: 2014-01-16, 公開日: 2014-04-02, 最終更新日: 2023-09-20)

主引用文献

Gonzalez, A.Z.,Li, Z.,Beck, H.P.,Canon, J.,Chen, A.,Chow, D.,Duquette, J.,Eksterowicz, J.,Fox, B.M.,Fu, J.,Huang, X.,Houze, J.,Jin, L.,Li, Y.,Ling, Y.,Lo, M.C.,Long, A.M.,McGee, L.R.,McIntosh, J.,Oliner, J.D.,Osgood, T.,Rew, Y.,Saiki, A.Y.,Shaffer, P.,Wortman, S.,Yakowec, P.,Yan, X.,Ye, Q.,Yu, D.,Zhao, X.,Zhou, J.,Olson, S.H.,Sun, D.,Medina, J.C.
Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres.
J.Med.Chem., 57:2963-2988, 2014

PubMed Abstract: We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

PubMed: 24601644
DOI: 10.1021/jm401911v

実験手法

X-RAY DIFFRACTION (1.377 Å)