ER/estrogen receptor; selective estrogen receptor degrader (SERD)
Imlunestrant tosylate targets the Estrogen Receptor (ER). As a SERD, it binds to ER and induces its degradation, resulting in sustained inhibition of ER-dependent gene transcription and cell growth. Its pure antagonistic properties mean it has no activating effects on the ER.

In ESR1 mutants, LY3484356 exhibits favorable pharmacokinetic (PK) characteristics, including antitumor activity [1].Estrogen receptor signalling has closely been tied to breast cancer progression and cancer cell proliferation. Estrogen receptor alpha (ERα) has been primarily implicated in breast cancer, and its activation promotes the expression of oncogenic factors that increase cancer cell proliferation, such as MYC, Cyclin D1, FOXM1, GREB1, BCL2 or amphiregulin, IGF-1 and CXCL12. Imlunestrant binds to ERα with high affinity and, in vitro, induces degradation of ERα: This leads to the inhibition of ER-dependent gene transcription and cellular proliferation in ER+ breast cancer cells. Imlunestrant is an estrogen receptor (ER) antagonist that induces degradation of ERα, leading to inhibition of ER-dependent gene transcription and cellular proliferation in ER+ breast cancer cells. Imlunestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.

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LY3484356, the active form of Imlunestrant, exhibits potent anti-proliferative activity in vitro against a panel of ER+ breast cancer cell lines, including those harboring ESR1 mutations (a common mechanism of resistance to standard endocrine therapies). It shows a good pharmacokinetic (PK) profile, including antitumor activity in ESR1 mutant models.

Imlunestrant demonstrated in vivo antitumour activity in ER+ breast cancer xenograft models, including models with ESR1 mutations. Imlunestrant is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon oral administration, imlunestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that results in ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells. Imlunestrant is able to cross the blood-brain barrier (BBB). IMLUNESTRANT is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 3 investigational indications.

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Imlunestrant tosylate demonstrates robust in vivo efficacy in ER+ xenograft models. It has shown the ability to induce tumor regression and cause sustained inhibition of tumor growth. Its oral bioavailability and potent SERD activity make it a promising candidate for preclinical and clinical research.

Cell-free ER binding assays are performed using a time-resolved fluorescence resonance energy transfer (TR-FRET) format. A GST-tagged ER ligand-binding domain, a terbium-labeled anti-GST antibody, and a fluorescein-labeled coactivator peptide are used. The compound's ability to competitively displace an agonist is measured, and the IC50 is determined by the loss of TR-FRET signal.

ER+ breast cancer cell lines (e.g., MCF-7, T47D) are seeded in 96-well plates and treated with a dilution series of Imlunestrant tosylate for 5-7 days. Cell viability is measured using the CellTiter-Glo luminescent cell viability assay, which quantifies ATP as a marker of metabolically active cells, to calculate the half-maximal inhibitory concentration (IC50) for growth inhibition.

In vivo efficacy is evaluated in female athymic nude mice bearing established ER+ MCF-7 breast cancer xenografts. Mice are randomized into treatment groups and receive Imlunestrant tosylate via oral gavage (p.o.) at various doses. Tumor volumes are measured bi-weekly with calipers. Endpoints include tumor growth inhibition (TGI), time to tumor progression, and analysis of ER target gene expression and ER protein levels in harvested tumor tissue.

Absorption
The mean (%CV) maximum concentration (Cmax) of imrenlastane was 141 ng/mL (45%), and the area under the concentration-time curve (AUC) was 2,400 ng·h/mL (46%). Administered once daily at doses ranging from 200 mg to 1,200 mg (equivalent to 0.5 to 3 times the approved recommended dose), both Cmax and AUC of imrenlastane increased proportionally with the dose. Steady-state was reached in approximately 6 days, with a cumulative AUC of 2.3 times. The absolute oral bioavailability following a single oral dose of 400 mg imrenlastane was 10% (32%). The median time (min, maxima) to reach maximum plasma concentration (Tmax) of imrenlastane was 4 (2, 8) hours. Following co-administration with a low-fat meal (approximately 475 calories, of which 13% fat, 16% protein, and 71% carbohydrates), the AUC of imrulenstra increased 2-fold, and the Cmax increased 3.6-fold. The effect of a high-fat meal (approximately 800-1000 calories, of which 500-600 calories are from fat) on imrulenstra exposure is unclear.
Elimination Route
Following a single dose of 400 mg of radiolabeled imrulenstra in healthy subjects, 97% of the dose was excreted in feces (62% unchanged) and 0.3% in urine.
Volume of Distribution
The apparent (oral) volume of distribution was 8120 L (69%).
Clearance
The estimated apparent clearance was 166 L/h (51%).
Protein Binding
The protein binding of imrulenstra is >99% and is concentration-independent.
Metabolism/Metabolites
Immulustae is primarily metabolized via CYP3A4-mediated sulfation and direct glucuronidation catalyzed by UGT1A1, 1A3, 1A8, 1A9, and 1A10. In a drug metabolism and disposal study, the metabolite with the highest plasma radioactivity was M1. Other metabolites with relatively identifiable radioactivity include M2 and M12.
Biological Half-Life
The elimination half-life of imulustae is 30 hours.

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Imlunestrant tosylate is characterized by its excellent oral bioavailability and favorable pharmacokinetic profile. It is designed to achieve high and sustained systemic exposure, allowing for continuous ER degradation. Its PK properties support a once-daily oral dosing regimen, which is a significant advantage over first-generation SERDs like fulvestrant.

Efficacy assessment was conducted in the EMBER-3 (NCT04975308) study, a randomized, open-label, positive-controlled, multicenter trial that enrolled 874 patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had previously received aromatase inhibitor monotherapy or combination therapy with CDK4/6 inhibitors. Patients eligible for PARP inhibitor therapy were excluded. Patients were randomized 1:1:1 to the imaxisome group, the investigator-selected endocrine therapy group (fulvestrant or exemestane), or an additional investigational combination therapy group. Randomization was stratified by prior CDK4/6 inhibitor therapy, presence of visceral metastases, and geographic region. ESR1 mutation status was determined by circulating tumor DNA (ctDNA) analysis using the Guardant360 CDx assay, limited to specific ESR1 mutations in the ligand-binding domain. The primary efficacy endpoint was investigator-assessed progression-free survival (PFS) (RECIST v1.1), comparing the efficacy of imirucept to investigator-selected endocrine therapy in patients with ESR1-mutant tumors. Other efficacy endpoints included overall survival (OS) and objective response rate (ORR). In the ESR1-mutant population (n=256), there was a statistically significant difference in investigator-assessed PFS between the imirucept group and the investigator-selected endocrine therapy group. The median PFS was 5.5 months in the imirucept group (95% CI: 3.9, 7.4) and 3.8 months in the investigator-selected endocrine therapy group (95% CI: 3.7, 5.5) (hazard ratio 0.62 [95% CI: 0.46, 0.82]; p = 0.0008). The objective response rate (ORR) was 14.3% in the imirucept group and 7.7% in the investigator-selected group. When performing progression-free survival (PFS) analysis, overall survival (OS) data were not yet mature, with a mortality rate of 31% in the ESR1 mutation population. The most common adverse events (≥10%) included abnormal laboratory findings, including decreased hemoglobin, musculoskeletal pain, decreased calcium, neutropenia, increased AST, fatigue, diarrhea, increased ALT, increased triglycerides, nausea, thrombocytopenia, constipation, increased cholesterol, and abdominal pain.

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Preclinical toxicology studies indicate that Imlunestrant tosylate is well-tolerated at therapeutic doses. The primary observed effects are on-target pharmacodynamic effects related to ER antagonism and degradation, such as changes in reproductive tissues. No significant off-target toxicities have been reported in preclinical models, supporting its potential for clinical research.

[1]. A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD) in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Results from the EMBER study. 2021 ASCO Annual Meeting I.

[2]. Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective. Int. J. Mol. Sci. 2021, 22(15), 7812.

Imlunestrant is a selective estrogen receptor antagonist and degrader that can cross the blood-brain barrier. On September 25, 2025, the U.S. Food and Drug Administration (FDA) approved Imlunestrant for the treatment of advanced or metastatic breast cancer with estrogen receptor (ER)-positive, HER2-negative, and estrogen receptor 1 (ESR1) mutations that has progressed after at least one line of endocrine therapy. Imlunestrant promotes ER degradation via the ubiquitin-proteasome pathway by antagonizing ER transcriptional activity and forming an unstable drug-receptor complex. In clinical trials, Imlunestrant has been used as monotherapy and in combination with other drugs in breast cancer patients. Imlunestrant is an estrogen receptor antagonist. Its mechanism of action includes acting as an estrogen receptor antagonist, a P-glycoprotein inhibitor, and an inhibitor of breast cancer resistance proteins.

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Imlunestrant tosylate is a next-generation oral SERD that has advanced into clinical trials. The EMBER study (Phase 1a/b) has investigated its use as a monotherapy and in combination with other agents (e.g., abemaciclib) for patients with ER+ advanced breast cancer. It represents a promising new class of endocrine therapy designed to overcome resistance to current treatments.

C36H32F4N2O6S

696.707702636719

696.191

C, 62.06; H, 4.63; F, 10.91; N, 4.02; O, 13.78; S, 4.60

2408840-41-3

Imlunestrant;2408840-26-4;(S)-Imlunestrant tosylate;2408840-43-5

156620226

White to light yellow solid powder

2

12

7

49

995

1

CC1=CC=C(C=C1)S(=O)(=O)O.C1C(CN1CCOC2=CC=C(C=C2)[C@@H]3C4=C5C=CC(=CC5=NC=C4C6=C(O3)C=C(C=C6)C(F)(F)F)O)CF

WOXQMUXFSMQUSS-LNLSOMNWSA-N

InChI=1S/C29H24F4N2O3.C7H8O3S/c30-13-17-15-35(16-17)9-10-37-21-5-1-18(2-6-21)28-27-23-8-4-20(36)12-25(23)34-14-24(27)22-7-3-19(29(31,32)33)11-26(22)38-28;1-6-2-4-7(5-3-6)11(8,9)10/h1-8,11-12,14,17,28,36H,9-10,13,15-16H2;2-5H,1H3,(H,8,9,10)/t28-;/m1./s1

(5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol;4-methylbenzenesulfonic acid

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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