5HMK

HDM2 in complex with a 3,3-Disubstituted Piperidine

5HMK の概要

• エントリーDOI: 10.2210/pdb5hmk/pdb
• 関連するPDBエントリー: 5HMH 5HMI
• 分子名称: E3 ubiquitin-protein ligase Mdm2, {4-[2-(2-hydroxyethoxy)phenyl]piperazin-1-yl}[(2R,3S)-2-propyl-3-[4-(trifluoromethyl)phenoxy]-1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}piperidin-3-yl]methanone (3 entities in total)
• 機能のキーワード: oncology, e3 ubiquitin-protein ligase, p53/tp53, 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: 2
• 化学式量合計: 26470.03

構造登録者

Scapin, G. (登録日: 2016-01-16, 公開日: 2016-04-06, 最終更新日: 2024-03-06)

主引用文献

Bogen, S.L.,Pan, W.,Gibeau, C.R.,Lahue, B.R.,Ma, Y.,Nair, L.G.,Seigel, E.,Shipps, G.W.,Tian, Y.,Wang, Y.,Lin, Y.,Liu, M.,Liu, S.,Mirza, A.,Wang, X.,Lipari, P.,Seidel-Dugan, C.,Hicklin, D.J.,Bishop, W.R.,Rindgen, D.,Nomeir, A.,Prosise, W.,Reichert, P.,Scapin, G.,Strickland, C.,Doll, R.J.
Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
Acs Med.Chem.Lett., 7:324-329, 2016

PubMed Abstract: A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

PubMed: 26985323
DOI: 10.1021/acsmedchemlett.5b00472

実験手法

X-RAY DIFFRACTION (2.17 Å)