6SBO

Estrogen receptor mutant L536S

Summary for 6SBO

• Entry DOI: 10.2210/pdb6sbo/pdb
• Descriptor: Estrogen receptor, 6-(2,4-dichlorophenyl)-5-[4-[(3~{S})-1-(3-fluoranylpropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7~{H}-benzo[7]annulene-2-carboxylic acid (3 entities in total)
• Functional Keywords: receptor, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 60326.70

Authors

Vallee, F.,Steier, V.,Rak, A. (deposition date: 2019-07-22, release date: 2019-11-27, Last modification date: 2024-05-15)

Primary citation

El-Ahmad, Y.,Tabart, M.,Halley, F.,Certal, V.,Thompson, F.,Filoche-Romme, B.,Gruss-Leleu, F.,Muller, C.,Brollo, M.,Fabien, L.,Loyau, V.,Bertin, L.,Richepin, P.,Pilorge, F.,Desmazeau, P.,Girardet, C.,Beccari, S.,Louboutin, A.,Lebourg, G.,Le-Roux, J.,Terrier, C.,Vallee, F.,Steier, V.,Mathieu, M.,Rak, A.,Abecassis, P.Y.,Vicat, P.,Benard, T.,Bouaboula, M.,Sun, F.,Shomali, M.,Hebert, A.,Levit, M.,Cheng, H.,Courjaud, A.,Ginesty, C.,Perrault, C.,Garcia-Echeverria, C.,McCort, G.,Schio, L.
Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer.
J.Med.Chem., 63:512-528, 2020

PubMed Abstract: More than 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), and resistance to current hormone therapies occurs in one-third of ER+ patients. Tumor resistance is still ERα-dependent, but mutations usually confer constitutive activation to the hormone receptor, rendering ERα modulator drugs such as tamoxifen and aromatase inhibitors ineffective. Fulvestrant is a potent selective estrogen receptor degrader (SERD), which degrades the ERα receptor in drug-resistant tumors and has been approved for the treatment of hormone-receptor-positive metastatic breast cancer following antiestrogen therapy. However, fulvestrant shows poor pharmacokinetic properties in human, low solubility, weak permeation, and high metabolism, limiting its administration to inconvenient intramuscular injections. This Drug Annotation describes the identification and optimization of a new series of potent orally available SERDs, which led to the discovery of 6-(2,4-dichlorophenyl)-5-[4-[(3)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7-benzo[7]annulene-2-carboxylic acid (), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.

PubMed: 31721572
DOI: 10.1021/acs.jmedchem.9b01293

Experimental method

X-RAY DIFFRACTION (1.48 Å)