SAR439859

SAR439859 is a selective estrogen receptor degrader (SERD).¹ It selectively induces degradation of estrogen receptor α (ERα) in MCF-7 breast cancer cells (EC₅₀ = 0.2 nM) over ERβ, glucocorticoid, androgen, progesterone, and mineralocorticoid receptors at 5 µM but does activate ERβ signaling in reporter cells.² SAR439859 decreases 17β-estradiol-induced proliferation of MCF-7 cells expressing wild-type ERα, MCF-7 cells expressing ERα containing a tyrosine-to-serine substitution at position 537 (ERα^Y537S), and MCF-7 cells expressing ERα^D538G (EC₅₀s = 20, 331, and 595 nM, respectively). In vivo, SAR439859 (100 mg/kg per day) reduces tumor volume to a greater extent than the ER degraders fulvestrant (Item No. 10011269) or GDC-0810 (ARN810; Item No. 29595) in a patient-derived xenograft (PDX) mouse model of breast cancer resistant to the ER antagonist tamoxifen (Item Nos. 13258 | 11629).

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1. El-Ahmad, Y., Tabart, M., Halley, F., et al. 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. 63(2), 512-528 (2020).

2. Shomali, M., Cheng, J., Sun, F., et al. SAR439859, a novel selective estrogen receptor degrader (SERD), demonstrates effective and broad antitumor activity in wild-type and mutant ER-positive breast cancer models. Mol. Cancer Ther. 20(2), 250-262 (2021).