ER/estrogen receptor

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.

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.

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.

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.

[1]. Selective estrogen receptor degraders. WO2020014435.

Estrogen receptor-positive (ER+) breast cancer is the most common subtype. Endocrine therapy is the cornerstone of treatment for this disease, acting by directly or indirectly regulating estrogen production. Significant progress has been made in the development of novel compounds in recent years, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and phosphatidylinositol 3-kinase (PI3K) inhibitors, which have significantly improved progression-free survival and overall survival in ER+ patients. However, some patients still develop resistance after or during endocrine therapy. Several potential mechanisms associated with endocrine therapy resistance have been identified, with ESR1 gene mutations being one of the most thoroughly investigated. Other mechanisms include somatic mutations, microenvironmental alterations, and epigenetic changes. Against this backdrop, selective estrogen receptor degraders/downregulators (SERDs) are currently one of the important approaches under development to combat resistance to aromatase inhibitors or tamoxifen. The first approved selective estrogen receptor antagonist (SERD) for the treatment of ER-positive breast cancer was fulvestrant, which also demonstrated remarkable efficacy in second-line treatment of ESR1-mutant patients. Recent advances in research have enabled the development of novel SERDs with higher oral bioavailability. This article reviews the development history and ongoing research of SERDs and novel anti-ER molecules, hoping that these new drugs will improve future treatment prospects for patients.

C36H32F4N2O6S

696.707702636719

696.191

C, 66.41; H, 4.61; F, 14.49; N, 5.34; O, 9.15

2408840-43-5

Imlunestrant;2408840-26-4;Imlunestrant tosylate;2408840-41-3

168006870

Off-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-JCOPYZAKSA-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-;/m0./s1

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

(S)-Imlunestrant tosylate; 2408840-43-5; (S)-Imlunestrant (tosylate); (S)-LY-3484356 (tosylate);

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.)