8DUI

Estrogen Receptor Alpha Ligand Binding Domain in Complex with (1'-(4-(2-(dimethylamino)ethoxy)phenyl)-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl)(phenyl)methanone

8DUI の概要

• エントリーDOI: 10.2210/pdb8dui/pdb
• 分子名称: Estrogen receptor, [(1'R)-1'-{4-[2-(dimethylamino)ethoxy]phenyl}-6'-hydroxy-1',4'-dihydro-2'H-spiro[cyclopropane-1,3'-isoquinolin]-2'-yl](phenyl)methanone (3 entities in total)
• 機能のキーワード: antiestrogen, breast cancer, alpha helical bundle, estrogen receptor, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 58951.13

構造登録者

Hancock, G.R.,Young, K.S.,Hosfield, D.J.,Joiner, C.,Sullivan, E.A.,Yildz, Y.,Laine, M.,Greene, G.L.,Fanning, S.W. (登録日: 2022-07-27, 公開日: 2022-11-09, 最終更新日: 2023-10-25)

主引用文献

Hancock, G.R.,Young, K.S.,Hosfield, D.J.,Joiner, C.,Sullivan, E.A.,Yildiz, Y.,Laine, M.,Greene, G.L.,Fanning, S.W.
Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells.
NPJ Breast Cancer, 8:130-130, 2022

PubMed Abstract: Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.

PubMed: 36517522
DOI: 10.1038/s41523-022-00497-9

実験手法

X-RAY DIFFRACTION (2.04 Å)