5U6D

Polycomb protein EED in complex with inhibitor: 2-[4-(4-{(3S,4R)-4-(dimethylamino)-1-[(2-fluoro-6-methylphenyl)methyl]pyrrolidin-3-yl}phenyl)-1H-pyrazol-1-yl]acetamide

5U6D の概要

• エントリーDOI: 10.2210/pdb5u6d/pdb
• 関連するPDBエントリー: 5U69
• 分子名称: Polycomb protein EED, 2-[4-(4-{(3S,4R)-4-(dimethylamino)-1-[(2-fluoro-6-methylphenyl)methyl]pyrrolidin-3-yl}phenyl)-1H-pyrazol-1-yl]acetamide (3 entities in total)
• 機能のキーワード: wd40 prc2, protein binding, inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O75530
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43019.02

構造登録者

Jakob, C.G.,Zhu, H. (登録日: 2016-12-07, 公開日: 2017-03-15, 最終更新日: 2023-10-04)

主引用文献

Curtin, M.L.,Pliushchev, M.A.,Li, H.Q.,Torrent, M.,Dietrich, J.D.,Jakob, C.G.,Zhu, H.,Zhao, H.,Wang, Y.,Ji, Z.,Clark, R.F.,Sarris, K.A.,Selvaraju, S.,Shaw, B.,Algire, M.A.,He, Y.,Richardson, P.L.,Sweis, R.F.,Sun, C.,Chiang, G.G.,Michaelides, M.R.
SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.
Bioorg. Med. Chem. Lett., 27:1576-1583, 2017

PubMed Abstract: Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model. X-ray crystal structures of several inhibitors bound in the EED active-site are also discussed.

PubMed: 28254486
DOI: 10.1016/j.bmcl.2017.02.030

実験手法

X-RAY DIFFRACTION (1.64 Å)