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
Over 75% of breast cancers are estrogen receptor alpha (ERα) positive (ER+), but one-third of ER+ patients develop resistance to current hormone therapies. While tumor resistance remains ERα-dependent, mutations typically lead to constitutive activation of the receptor, making ERα modulators like tamoxifen and aromatase inhibitors ineffective. Fulvestrant, a potent selective estrogen receptor degrader (SERD), works by degrading the ERα receptor in drug-resistant tumors and is approved for the treatment of hormone-receptor-positive metastatic breast cancer after antiestrogen therapy. However, fulvestrant has poor pharmacokinetic properties in humans, including low solubility, weak permeation, and rapid metabolism, which limits its use to inconvenient intramuscular injections. This Drug Annotation outlines the identification and optimization of a new series of potent orally available SERDs, culminating in 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). This compound demonstrated promising antitumor activity in breast cancer mouse xenograft models and has properties suitable for clinical evaluation.