ERα (IC50 = 48 nM), ERβ (IC50 = 870 nM)[1]
Elacestrant targets the estrogen receptor (ER), specifically both ERα and ERβ isoforms. As a selective estrogen receptor degrader (SERD), it binds to the ER and promotes its degradation via the proteasome, thereby inhibiting ER-mediated signaling. The compound has IC50 values of 48 nM for ERα and 870 nM for ERβ. By degrading the receptor, it prevents estrogen-driven proliferation of ER+ breast cancer cells and overcomes resistance associated with ESR1 mutations.

The concentration-dependent inhibition of ERα expression in MCF-7 cells (EC50 = 0.6 nM) is observed with elacestrant dihydrochloride (RAD1901; 0.5 nM-10 µM; 48 h) [1]. 48 hours of elacestrant dihydrochloride (0–1 µM). is shown to have concentration-dependent antiproliferative action (EC50 = 4 pM) on ER-acute MCF-7 cells triggered by estradiol (E2) [1]. Progesterone receptors (PGR, PR, and an ER) in MCF7 and T47D cell lines are reduced by elacestrant diHCl (0–1 µM; 24 or 48 hours).
In vitro, Elacestrant inhibits the expression of ERα and ERβ in cultured breast tumor cell lines, resulting in dose-dependent inhibition of cell proliferation. It induces degradation of ER and inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines. The compound shows potent antiproliferative activity against ER-positive breast cancer cells, including those with ESR1 mutations that confer resistance to other endocrine therapies. Its IC50 values for ERα and ERβ are 48 and 870 nM, respectively.

Elecestrant dihydrochloride multiplexes anti-E2-mediated promotion of proliferation in a dose-dependent manner (0.3-120 mg/kg; po; once daily for 40 days) [1]. Even if elacestrant diHCl is totally stopped, tumor growth inhibition may persist [2].
In vivo, Elacestrant significantly inhibits tumor growth in multiple patient-derived xenograft (PDX) models of ER+ breast cancer. In MCF-7 xenograft models, animals treated with Elacestrant have longer survival times than control groups or those treated with fulvestrant (ICI 182780). It also protects against ovariectomy-induced bone loss and prevents estradiol (E2)-induced uterine trophic effects. These in vivo findings support its efficacy and favorable safety profile for treating ER+ breast cancer.

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 receptor binding assays for Elacestrant involve competitive binding to estrogen receptor α and β. Radiolabeled estradiol is used as a tracer, and the compound's ability to displace the tracer from ER is measured. IC50 values for ERα and ERβ are calculated from competition curves. Functional assays include assessment of ER degradation by Western blotting in ER+ breast cancer cell lines treated with the compound, as well as reporter gene assays measuring ER transcriptional activity.

Cell proliferation assay [1]
Cell Types: ER-positive MCF-7 cells (estradiol (E2) stimulation)
Tested Concentrations: 0-1 μM
Incubation Duration: 48 hrs (hours)
Experimental Results: Anti-proliferative activity was shown. cell.

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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.
Cellular assays for Elacestrant utilize ER-positive breast cancer cell lines such as MCF-7 or T47D. Cells are treated with various concentrations of Elacestrant for defined periods (24-72 hours). Cell proliferation is measured using MTT, CCK-8, or ATP-lite assays. ER protein levels are assessed by Western blotting to confirm receptor degradation. ER transcriptional activity is evaluated using luciferase reporter constructs. Apoptosis is assessed by caspase-3/7 activity or Annexin V staining.

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 utilize MCF-7 xenograft models in immunodeficient mice, often supplemented with estradiol to support tumor growth. Patient-derived xenograft (PDX) models of ER+ breast cancer are also used. The compound is administered orally at various doses. Tumor volume is measured twice weekly, and survival is monitored. Bone density and uterine weight are assessed to evaluate on-target and off-target effects. Pharmacodynamic endpoints include ER degradation in tumor tissue.

Absorption
At the recommended 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 the oral bioavailability is approximately 10%. Compared to the 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.
Elimination Pathway
Irastar is primarily excreted in feces and urine. Following a single oral dose of 345 mg of radiolabeled irastar, approximately 82% is excreted in feces (34% unchanged) and 7.5% in urine (<1% unchanged).
Volume of Distribution
The apparent volume of distribution of irastar is 5800 L.
Clearance
The estimated clearance of irastar is 186 L/hr, with renal clearance ≤0.14 L/hr.

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Metabolism/Metabolites
Irastar is metabolized in the liver, primarily via CYP3A4, with minor amounts metabolized via CYP2A6 and CYP2C9.

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Biological Half-Life
The elimination half-life of irastar is 30 to 50 hours.
Elacestrant is orally bioavailable with favorable pharmacokinetic properties. As a small molecule SERD, it is administered orally once daily. It undergoes hepatic metabolism, and its pharmacokinetic profile supports once-daily dosing. The compound's oral bioavailability and favorable half-life enable convenient oral administration compared to intramuscular fulvestrant. Detailed PK parameters (Cmax, AUC, t1/2) have been characterized in clinical trials. Food effects on absorption may be evaluated as part of clinical pharmacology studies.

Protein binding rate: Elacestrant has a plasma protein binding rate of over 99%, which is independent of concentration.
In clinical trials, Elacestrant is generally well-tolerated. Common adverse effects include nausea, fatigue, musculoskeletal pain, and decreased appetite, consistent with other endocrine therapies. The compound has a favorable safety profile compared to fulvestrant, with no injection site reactions due to oral administration. Hepatic and renal function are monitored. The EMERALD Phase 3 trial demonstrated significantly improved progression-free survival in patients with ESR1-mutated tumors, leading to regulatory approval.

[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.

Elacestrant hydrochloride is the hydrochloride form of Elacestrant, an orally potent selective estrogen receptor degrader (SERD) with antitumor activity. After oral administration, Elacestrant, as a SERD, binds to the estrogen receptor (ER), inducing a conformational change that leads to receptor degradation by the proteasome. This blocks ER-mediated signaling and inhibits the proliferation of ER-expressing cancer cells.
See also: Elacestrant (note moved to); Elacestrant dihydrochloride (note moved to).
Elacestrant dihydrochloride (RAD-1901) is a first-in-class oral SERD approved for ER+/HER2- advanced or metastatic breast cancer with ESR1 mutations. It binds to ER and induces proteosomal degradation. Clinical trials (EMERALD) showed significant PFS benefit. The compound is orally administered and represents an important advance over injectable SERDs like fulvestrant.

C30H40CL2N2O2

531.5568

530.246

C, 67.79; H, 7.59; Cl, 13.34; N, 5.27; O, 6.02

1349723-93-8

Elacestrant;722533-56-4;Elacestrant S enantiomer dihydrochloride;2309762-30-7;Elacestrant (S enantiomer);2309762-29-4

67479909

White to off-white solid powder

4

4

10

36

578

1

CCNCCC1=CC=C(C=C1)CN(CC)C2=C(C=CC(=C2)OC)[C@@H]3CCC4=C(C3)C=CC(=C4)O.Cl.Cl

XGFHYCAZOCBCRQ-FBHGDYMESA-N

InChI=1S/C30H38N2O2.2ClH/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,4-5,10-11,16-18,21H2,1-3H32*1H/t26-/m1../s1

(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride

RAD1901 dihydrochloride; RAD-1901; Elacestrant dihydrochloride; 1349723-93-8; RAD1901 dihydrochloride; Elacestrant (dihydrochloride); Elacestrant hydrochloride; RAD1901 hydrochloride; 8NZT0PR8AL; ORSERDU; RAD 1901; RAD1901 HCl salt; Elacestrant

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, avoid exposure to moisture.

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

DMSO : ~100 mg/mL (~188.13 mM)
H2O : ~50 mg/mL (~94.06 mM)

Solubility in Formulation 1: ≥ 2.87 mg/mL (5.40 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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: ≥ 2.87 mg/mL (5.40 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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: ≥ 2.5 mg/mL (4.70 mM) 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 25.0 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 4: ≥ 2.5 mg/mL (4.70 mM) 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 25.0 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 5: ≥ 2.5 mg/mL (4.70 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 6: ≥ 0.57 mg/mL (1.07 mM) (saturation unknown) in 1% DMSO + 99% Saline (add these co-solvents sequentially from left to right, and one by one),clear solution.

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