1. 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
- Author
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Chrystelle Girardet, Magali Mathieu, François Vallée, Jacques Le-Roux, Fangxian Sun, Laurence Fabien, Corinne Terrier, Celine Ginesty, Bruno Filoche-Romme, Florence Gruss-Leleu, Maysoun Shomali, Monsif Bouaboula, Sylvie Beccari, Pascal Desmazeau, Gilles Lebourg, Tsiala Benard, Victor Certal, Pascale Vicat, Andrew Hebert, Carlos Garcia-Echeverria, Laurent Schio, Youssef El-Ahmad, Gary Mccort, Claire Muller, Maurice Brollo, Mikhail Levit, Luc Bertin, Hong Cheng, Véronique Loyau, Valerie Steier, Fabienne Thompson, Audrey Louboutin, Fabienne Pilorge, Alexey Rak, Frank Halley, Patrick Richepin, Christelle Perrault, Pierre-Yves Abecassis, Michel Tabart, and Albane Courjaud
- Subjects
0303 health sciences ,biology ,Fulvestrant ,Chemistry ,Estrogen receptor ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Breast cancer ,Hormone receptor ,Drug Discovery ,biology.protein ,medicine ,Cancer research ,Molecular Medicine ,Aromatase ,Receptor ,Estrogen receptor alpha ,Tamoxifen ,030304 developmental biology ,medicine.drug - 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-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (43d), showing promising antitumor activity in breast cancer mice xenograft models and whose properties warranted clinical evaluation.
- Published
- 2019