5UFX

Estrogen Receptor Alpha Ligand Binding Domain in Complex with OP1074

Summary for 5UFX

• Entry DOI: 10.2210/pdb5ufx/pdb
• Descriptor: Estrogen receptor, (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-1-benzopyran-7-ol (3 entities in total)
• Functional Keywords: breast cancer, estrogen, steroid, acquired resistance, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 57625.54

Authors

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. (deposition date: 2017-01-06, release date: 2018-01-10, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.5503 Å)