6WOK

Crystal structure of estrogen receptor alpha in complex with receptor degrader 6

6WOK の概要

• エントリーDOI: 10.2210/pdb6wok/pdb
• 分子名称: Estrogen receptor, (2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol, (1R,3R)-1-(2,6-difluoro-4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline, ... (4 entities in total)
• 機能のキーワード: era, antagonist, inverse agonist, receptor, breast cancer, degrader, ligand, estrogen receptor, nuclear protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 130800.72

構造登録者

Kiefer, J.R.,Vinogradova, M.,Liang, J.,Zhang, B.,Wang, X.,Labadie, S. (登録日: 2020-04-24, 公開日: 2020-07-01, 最終更新日: 2023-11-01)

主引用文献

Liang, J.,Blake, R.,Chang, J.,Friedman, L.S.,Goodacre, S.,Hartman, S.,Ingalla, E.R.,Kiefer, J.R.,Kleinheinz, T.,Labadie, S.,Li, J.,Lai, K.W.,Liao, J.,Mody, V.,McLean, N.,Metcalfe, C.,Nannini, M.,Otwine, D.,Ran, Y.,Ray, N.,Roussel, F.,Sambrone, A.,Sampath, D.,Vinogradova, M.,Wai, J.,Wang, T.,Yeap, K.,Young, A.,Zbieg, J.,Zhang, B.,Zheng, X.,Zhong, Y.,Wang, X.
Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Acs Med.Chem.Lett., 11:1342-1347, 2020

PubMed Abstract: Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of that showed ionic interaction of azetidine with Asp351 residue. Importantly, showed favorable metabolic stability and good oral exposure. exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.

PubMed: 32551022
DOI: 10.1021/acsmedchemlett.0c00224

実験手法

X-RAY DIFFRACTION (2.309 Å)