SAR439859 (Amcenestrant) is an orally active, nonsteroidal and selective degrader of estrogen receptor, it is also a potent antagonist of ER with EC50 of 0.2 nM for ERα degradation. SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, including inhibition of ER signaling and tumor cell growth.
In vivo treatment with SAR439859 demonstrates significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. SAR439859 (2.5-25 mg/kg; orally twice daily for 30 days) exhibits substantial tumor-growth inhibition and displays tumor regression at the dose of 25 mg/kg/BID.
|Cell lines||LCC2 cells, MCF7 cells|
|Preparation method||Trypsinized cells are dispensed into 384-well plates in IMEM (supplemented with 5% FBS) and after overnight incubation cells are treated with SAR439859 for the times indicated. Cell viability is assessed using CellTiter-Glo according to the manufacturer’s protocol and relative luminescence units (RLU) are measured using an Envision Multilabel Reader. The RLUs of the treated samples are normalized to that of the untreated samples and cell viability is expressed as a percentage of the value of the untreated cells.|
|Incubation time||7 days, 4 hours|
|Animal models||Nu/nu mouse with MCF7 tumor xenograft model|
|Formulation||solution (0.6 mg/mL) in glycofurol/PS80/G5 (10%/5%/85%) and solution (1 mg/mL) in labrasol/solutol/G5 (20%/5%/75%)|
|Dosages||2.5, 5, 12.5, 25 mg/kg|
|Administration||Orally; twice daily for 30 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 80 mg/mL|
SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models
Maysoun Shomali, et al. Mol Cancer Ther. 2021 Feb;20(2):250-262. PMID: 33310762.
Discovery of 6-(2,4-Dichlorophenyl)-5-[4-[(3 S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7 H-benzoannulene-2-carboxylic acid (SAR439859), a Potent and Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen-Receptor-Positive Breast Cancer
Youssef El-Ahmad, et al. J Med Chem. 2020 Jan 23;63(2):512-528. PMID: 31721572.
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