5UFW

Estrogen Receptor Alpha Ligand Binding Domain in Complex with OP1154

5UFW の概要

• エントリーDOI: 10.2210/pdb5ufw/pdb
• 分子名称: Estrogen receptor, (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3S)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-1-benzopyran-7-ol (3 entities in total)
• 機能のキーワード: estrogen, breast cancer, hormone, nuclear hormone 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: 57625.54

構造登録者

Fanning, S.W.,Hodges-Gallagher, L.,Myles, D.C.,Sun, R.,Fowler, C.E.,Green, B.D.,Harmon, C.L.,Greene, G.L.,Kushner, P.J. (登録日: 2017-01-06, 公開日: 2018-01-10, 最終更新日: 2023-10-04)

主引用文献

Fanning, S.W.,Hodges-Gallagher, L.,Myles, D.C.,Sun, R.,Fowler, C.E.,Plant, I.N.,Green, B.D.,Harmon, C.L.,Greene, G.L.,Kushner, P.J.
Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity.
Nat Commun, 9:2368-2368, 2018

PubMed Abstract: Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.

PubMed: 29915250
DOI: 10.1038/s41467-018-04413-3

実験手法

X-RAY DIFFRACTION (1.583 Å)