ERα (IC50 = 48 nM), ERβ (IC50 = 870 nM)[1]

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 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 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.

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.

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.

Absorption, Distribution and Excretion
With the recommended dosage of 345 mg once daily, elacestrant has a steady-state Cmax of 119 ng/mL and an AUC0-24h of 2440 ng⋅h/mL. The Cmax and AUC of elacestrant increase more than dose-proportional between 43 mg and 862 mg once daily (0.125 to 2.5 times the approved recommended dosage). By day 6, elacestrant reaches steady-state and has a 2-fold mean accumulation ratio based on AUC0-24h. The tmax of elacestrant goes from 1 to 4 hr, and its oral bioavailability is approximately 10%. Compared to a fasted state, the Cmax and AUC of elacestrant (345 mg) were 42% and 22% higher, respectively, when administered with a high-fat meal (800 to 1000 calories, 50% fat).
Elacestrant is mainly eliminated through feces and urine. Approximately 82% was recovered in feces (34% unchanged), and 7.5% was recovered in urine (< 1% unchanged) following a single radiolabeled oral dose of 345 mg.
Elacestrant has an apparent volume of distribution of 5800 L.
Elacestrant has an estimated clearance of 186 L/hr and a renal clearance of ≤ 0.14 L/hr.

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Metabolism / Metabolites
Elacestrant is metabolized in the liver, mainly by CYP3A4 and, to a lesser extent, by CYP2A6 and CYP2C9.

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Biological Half-Life
The elimination half-life of elacestrant is 30 to 50 hours.

Protein Binding
Elacestrant has a protein plasma binding higher than 99% and independent of concentration.

[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 relationships and pharmacodynamics time course of elacestrant have not been fully characterized. At the approved recommended dose, the use of elacestrant does not lead to QTc interval increases higher than 20 msec. Hypercholesterolemia and hypertriglyceridemia have occurred in patients taking elacestrant, and administering this drug to pregnant women may cause fetal harm. Unlike other selective estrogen receptor modulators and degraders, elacestrant is capable of crossing the blood-brain barrier.

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.)