1. Academic Validation
  2. Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3 S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7 H-benzo[7]annulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer

Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3 S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7 H-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. 2020 Jan 23;63(2):512-528. doi: 10.1021/acs.jmedchem.9b01293.
Youssef El-Ahmad Michel Tabart Frank Halley Victor Certal Fabienne Thompson Bruno Filoche-Rommé Florence Gruss-Leleu Claire Muller Maurice Brollo Laurence Fabien Véronique Loyau Luc Bertin Patrick Richepin Fabienne Pilorge Pascal Desmazeau Chrystelle Girardet Sylvie Beccari Audrey Louboutin Gilles Lebourg Jacques Le-Roux Corinne Terrier François Vallée Valérie Steier Magali Mathieu Alexey Rak Pierre-Yves Abecassis Pascale Vicat Tsiala Benard Monsif Bouaboula 1 Fangxian Sun 1 Maysoun Shomali 1 Andrew Hebert 1 Mikhail Levit 1 Hong Cheng 1 Albane Courjaud Celine Ginesty Christelle Perrault Carlos Garcia-Echeverria Gary McCort Laurent Schio
Affiliations

Affiliation

  • 1 Oncology , Sanofi , 640 Memorial Drive , Cambridge , Massachusetts 02139 , United States.
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.

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