ERα (IC50 = 48 nM), ERβ (IC50 = 870 nM)[1]
Elacestrant targets the estrogen receptor (ER), specifically ERα and ERβ. As a selective estrogen receptor degrader (SERD), it binds to the estrogen receptor and causes its degradation, leading to a decrease in estrogen signaling. It has IC₅₀ values of 48 and 870 nM for ERα and ERβ, respectively. By degrading the ER, it prevents estrogen from binding to the receptor and activating downstream signaling pathways involved in cell proliferation and survival. This makes it effective against ER-positive breast cancer, particularly in tumors with ESR1 mutations that confer resistance to other endocrine therapies.

Elacestrant (RAD1901; 0.5 nM-10 µM; 48 h) suppresses ERα expression in MCF-7 cells in a concentration-dependent manner (EC50 = 0.6 nM)[1]. Elacestrant (0-1 µM; 48 h) showed anti-proliferative action (EC50 = 4 pM) against estradiol (E2)-stimulated ER-positive MCF-7 cells in a concentration-dependent manner [1]. Elacestrant (0-1 µM; 24 or 48 h) in MCF7, T47D Elacestrant (0.01, 0.1, 1.0 µM) lowers the expression of progesterone receptors (PGR, PR; an ER target gene) in MCF7 and T47D cell lines [2].
In vitro, Elacestrant is a potent antagonist of ER-positive breast cancer cell proliferation with an IC₅₀ of 4.2 nM. It selectively binds to and degrades the estrogen receptor, with IC₅₀ values of 48 and 870 nM for ERα and ERβ, respectively. Its activity is typically assessed in cell-based proliferation assays using ER-positive breast cancer cell lines such as MCF-7. The compound's ability to degrade the ER is confirmed by Western blotting. Its selectivity for ERα over ERβ is an important feature for its therapeutic efficacy and safety profile.

In a dose-dependent manner, elacestrant (0.3-120 mg/kg; po; once daily for 40 days) inhibits E2-mediated intellectual stimulation [1]. Elacetrant (30, 60 mg/kg; po; 10 days per day). Even after the medicine is stopped, elacestrant can still stop tumor growth [2].
In vivo, Elacestrant has been evaluated in clinical trials and is approved for the treatment of ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Its oral bioavailability and efficacy have been demonstrated in clinical studies. The compound's ability to degrade the ER and inhibit tumor growth makes it a valuable therapeutic option for patients with endocrine-resistant breast cancer. It is also being studied for its potential use in other ER-positive cancers.

In vitro binding assays[2]
In vitro binding affinity of elacestrant was determined using purified ligand-binding domain of wild-type and mutant ERα in the PolarScreen ERα Competitor Assay as per manufacturer's instructions.
In vitro non-cell enzyme/receptor binding assays for Elacestrant involve measuring its binding affinity to the estrogen receptor (ERα and ERβ). Radioligand binding studies using membrane preparations or purified receptors and a labeled ligand (e.g., [³H]estradiol) are used to determine its IC₅₀ values of 48 and 870 nM for ERα and ERβ, respectively. Its ability to degrade the ER can be assessed in cell-free systems measuring protein stability.

Cell proliferation assay [1]
Cell Types: ER-positive MCF-7 cells (estradiol (E2)-stimulated) [1]
Tested Concentrations: 0-1 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: demonstrated anti-proliferative activity on cells. .

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Western Blot Analysis[1]
Cell Types: MCF-7 Cell
Tested Concentrations: 0.5 nM-10 µM
Incubation Duration: 48 hrs (hours)
Experimental Results: Inhibition of ERα expression in a dose-dependent manner (EC50 of 0.6 nM).

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Western Blot Analysis[2]
Cell Types: MCF7, T47D and HCC1428 Cell
Tested Concentrations: 0-1 µM
Incubation Duration: 24 or 48 hrs (hours)
Experimental Results: diminished estrogen receptor protein expression.
In vitro cell-based assays for Elacestrant use ER-positive breast cancer cell lines such as MCF-7. Cells are treated with varying concentrations of the compound, and cell proliferation is assessed using MTT or similar assays to determine the IC₅₀ of 4.2 nM. The compound's ability to degrade the ER is assessed by Western blotting for ER protein levels. Its effects on estrogen-responsive gene expression are measured by qPCR. These studies help to characterize the compound's mechanism of action and potency.

Animal/Disease Models: Mouse MCF7 cell line xenograft model [2].
Doses: 30, 60 mg/kg
Route of Administration: Oral; one time/day for 4 weeks
Experimental Results: Inhibition of tumor growth.

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In vivo xenograft experiments[2]
Female athymic nude mice (NU(NCr)-Foxn1nu or BALB/cAnNCrl-Foxn1nu) were acclimated for 3 to 7 days prior to implantation. Mice were given water (reverse osmosis, 1 ppm Cl) and fed a daily complete diet ad libitum, and were housed on irradiated bedding on a 12- to 14-hour light cycle under controlled temperature and humidity. Preformulated, clinical-grade fulvestrant (Faslodex) was obtained through third party vendors and administered by subcutaneous injection once weekly. Elacestrant, palbociclib and everolimus were administered daily by oral gavage. In the ST941 study, groups receiving palbociclib were initially administered 100 mg/kg and dose reduced to 75 mg/kg on day 14 of treatment. At the end of this study, average body weight loss for all treatment groups did not exceed 15%.

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MCF-7 xenografts.[2]
Twenty-four hours prior to implantation of MCF-7 cells, estrogen pellets (0. 18 mg/pellet 17β−estradiol, 90-day release) were implanted subcutaneously between the scapulae of female athymic nude mice using a sterilized trochar. MCF7 cells (5 × 106 per mouse) in 50:50 Matrigel:MEM were implanted in the rear flank. When mean tumor volumes reached approximately 150 to 200 mm3, mice were randomized to treatment groups based on tumor size. For pharmacodynamic analyses, MCF7 xenograft-bearing mice were treated daily for seven days, animals were euthanized, and tumors collected 4 and 24 hours post-last dose.

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Patient-derived xenograft models.[2]
HBCx-21, HBCx-3 and HBCx-19 patient-derived tumor xenografts (PDX) were derived at and studies run at XenTech. The ST986, ST941, and ST2177 PDX models were derived at and studies run at South Texas Accelerated Research Therapeutics. MAXF-713 was derived at and studies run at Charles River Discovery. All animals were subcutaneously implanted with PDX models and began receiving estrogen supplementation in the drinking water from the date of tumor implant to the end of the study. The HBCx-19, HBCx-3, and HBCx-21 models were supplemented with 8.5 milligrams of 17β-estradiol to each liter of drinking water. The MAXF-713 model was supplemented with 10 milligrams of 17β-estradiol to each liter of drinking water. When tumors grew to 150–200 mm3, mice were randomized on the basis of tumor volume and administered the indicated treatments. At the end of study, tumors were harvested 4 hours post-last dose unless otherwise indicated.

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In vivo pharmacokinetic analyses[2]
Terminal plasma was collected via heart puncture and nonterminal plasma was collected via orbital bleeding. For all mice, blood samples were collected in potassium-EDTA–containing tubes and processed for pharmacokinetic analysis. Analysis of fulvestrant in mouse plasma samples was carried out using high-performance liquid chromatography on a Pursuit XRs 3 Diphenyl 100 × 2.0 mm column.
In vivo animal studies for Elacestrant employ xenograft models using ER-positive breast cancer cell lines. The compound is administered orally, and tumor growth is monitored. Parameters such as tumor volume, tumor weight, and survival are recorded. Tumor tissues are analyzed for ER degradation and markers of cell proliferation and apoptosis. Pharmacokinetic studies in these models provide information about the compound's absorption, distribution, metabolism, and excretion. Clinical trials have also established its efficacy in patients with ESR1-mutated breast cancer.

Absorption, Distribution and Excretion
At the recommended once-daily dose of 345 mg, the steady-state Cmax of elacestrant is 119 ng/mL, and the AUC0-24h is 2440 ng⋅h/mL. At once-daily doses of 43 mg to 862 mg (equivalent to 0.125 to 2.5 times the approved recommended dose), the Cmax and AUC of elacestrant increase more than proportionally to the dose. By day 6, elacestrant reaches steady state with a mean cumulative ratio based on AUC0-24h of 2-fold. The tmax of elacestrant is 1 to 4 hours, and its oral bioavailability is approximately 10%. Compared to a fasting state, when co-administered with a high-fat meal (800 to 1000 calories, 50% fat), the Cmax and AUC of elacestrant (345 mg) increase by 42% and 22%, respectively. Irasilant is primarily excreted via feces and urine. Following a single oral dose of 345 mg of the radiolabeled drug, approximately 82% is excreted in feces (34% unchanged) and 7.5% in urine (<1% unchanged). The apparent volume of distribution of irasilant is 5800 L. The estimated clearance of irasilant is 186 L/hr, with renal clearance ≤0.14 L/hr. Metabolites are primarily metabolized in the liver, mainly via CYP3A4, with smaller amounts via CYP2A6 and CYP2C9. The elimination half-life of irasilant is 30 to 50 hours.
Elacestrant has a molecular weight of 458.65 g/mol and a molecular formula of C₃₀H₃₈N₂O₂. It is also known as RAD1901. The compound is orally bioavailable and is administered as a tablet. Its pharmacokinetic profile supports once-daily dosing. It is primarily metabolized in the liver and excreted in the feces. The compound should be stored under appropriate conditions, typically at room temperature, protected from light and moisture.

Protein Binding
Elacestrant exhibits plasma protein binding rates exceeding 99%, independent of concentration.
Elacestrant is generally well-tolerated, with side effects including hot flashes, fatigue, nausea, and joint pain. More serious side effects may include liver enzyme elevation and thromboembolic events. It is contraindicated in patients with a history of hypersensitivity to Elacestrant or any of its components. Its use during pregnancy and lactation is not recommended due to the risk of fetal harm.

[1]. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015 Oct;26(9):948-56.

[2]. Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models. Clin Cancer Res. 2017 Aug 15;23(16):4793-4804.

Pharmacodynamics
The exposure-response relationship and pharmacodynamic time course of erasetelin have not been fully elucidated. At the approved recommended dose, erasetelin does not cause a QTc interval prolongation exceeding 20 ms. Patients taking erasetelin have a history of hypercholesterolemia and hypertriglyceridemia; this medication may be harmful to the fetus in pregnant women. Unlike other selective estrogen receptor modulators and degraders, erasetelin can cross the blood-brain barrier.
Elacestrant (RAD1901) is an orally available and selective estrogen receptor degrader (SERD). It is an anticancer medication used to treat ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. It has IC₅₀ values of 48 and 870 nM for ERα and ERβ, respectively. It is an approved therapeutic agent in the United States and other countries.

C₃₀H₃₈N₂O₂

458.63

458.293

C, 78.56; H, 8.35; N, 6.11; O, 6.98

722533-56-4

Elacestrant dihydrochloride;1349723-93-8;Elacestrant S enantiomer dihydrochloride;2309762-30-7;Elacestrant (S enantiomer);2309762-29-4

23642301

White to off-white solid powder

1.1±0.1 g/cm3

609.5±55.0 °C at 760 mmHg

322.4±31.5 °C

0.0±1.8 mmHg at 25°C

1.604

7.07

2

4

10

34

578

1

O(C([H])([H])[H])C1C([H])=C([H])C(=C(C=1[H])N(C([H])([H])C([H])([H])[H])C([H])([H])C1C([H])=C([H])C(C([H])([H])C([H])([H])N([H])C([H])([H])C([H])([H])[H])=C([H])C=1[H])[C@@]1([H])C([H])([H])C2C([H])=C([H])C(=C([H])C=2C([H])([H])C1([H])[H])O[H]

SIFNOOUKXBRGGB-AREMUKBSSA-N

InChI=1S/C30H38N2O2/c1-4-31-17-16-22-6-8-23(9-7-22)21-32(5-2)30-20-28(34-3)14-15-29(30)26-11-10-25-19-27(33)13-12-24(25)18-26/h6-9,12-15,19-20,26,31,33H,4-5,10-11,16-18,21H2,1-3H3/t26-/m1/s1

(6R)-6-[2-[ethyl-[[4-[2-(ethylamino)ethyl]phenyl]methyl]amino]-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

RAD1901; RAD-1901; Elacestrant; 722533-56-4; ER-306323; elacestrantum; Elacestrant [INN]; Elacestrant [USAN];RAD 1901O; rserdu

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~160 mg/mL (~348.87 mM)

Solubility in Formulation 1: ≥ 4 mg/mL (8.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 40.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 4 mg/mL (8.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 40.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 4 mg/mL (8.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 40.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)