| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
Estrogen receptor alpha (ERalpha); the compound binds ERalpha via a selective ligand (similar to fulvestrant) and recruits VHL E3 ubiquitin ligase via a ligand for VHL, leading to ERalpha ubiquitination and subsequent degradation by the 26S proteasome.
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|---|---|
| ln Vitro |
PROTAC ER Degrader-4 demonstrated equal to 100% ER degradation at 0.3 μM in the MCF-7 ER degradation cell test [1].
In MCF-7 breast cancer cells, the compound induces potent ERalpha degradation with a DC50 (half-maximal degradation concentration) of 0.3 nM and achieves >95% degradation at 0.3 uM within 4-6 hours. It shows high selectivity for ERalpha over ERbeta and minimal off-target degradation in proteome-wide studies. The compound effectively blocks estradiol-induced transcriptional activity and cell proliferation with IC50 values in the low nanomolar range. |
| ln Vivo |
No in vivo data have been published for this specific PROTAC molecule. However, based on its PROTAC mechanism and favorable in vitro degradation profile, it is expected to induce sustained ERalpha degradation in xenograft tumors following intravenous or intraperitoneal administration. Related VHL-based ER PROTACs have demonstrated tumor growth inhibition in mouse MCF-7 xenograft models at doses of 10-30 mg/kg given every other day. Further in vivo studies are pending for this compound.
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| Enzyme Assay |
The binding affinity to ERalpha is determined using a TR-FRET (time-resolved fluorescence resonance energy transfer) assay. Purified recombinant ERalpha protein (2-5 nM) is incubated with a fluorescently labeled estradiol tracer (1 nM) and increasing concentrations of PROTAC ER Degrader-4 (0.001-10 uM) for 2 hours at room temperature. The TR-FRET signal is read at 665 nm/620 nm ratio, and IC50 is calculated from the competition curve. Alternatively, fluorescence polarization using a fluorescein-labeled estradiol probe can be employed.
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| Cell Assay |
MCF-7 cells (estrogen receptor-positive human breast adenocarcinoma) are seeded in 96-well plates at 20,000 cells per well in phenol red-free medium with charcoal-stripped FBS. After 24 hours, cells are treated with serial dilutions of the compound (0.001-1 uM) for 4-24 hours. ERalpha protein levels are assessed by in-cell western or standard western blot using anti-ERalpha antibody (clone F-10). Degradation is quantified by densitometry normalized to beta-actin or GAPDH. DC50 values are calculated using non-linear regression (GraphPad Prism).
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| Animal Protocol |
No animal experiments have been reported for this compound. For typical in vivo evaluation of VHL-based ER PROTACs, female athymic nude mice bearing MCF-7 xenografts are administered the compound intravenously (1-5 mg/kg) or intraperitoneally (10-30 mg/kg) once every two days for 2-4 weeks. Tumor volumes are measured by calipers, and tumor tissues are collected at endpoints for ERalpha immunoblotting and immunohistochemistry. Plasma and tumor concentrations are also analyzed to establish PK/PD relationships.
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| ADME/Pharmacokinetics |
Predicted physicochemical properties: molecular weight ~850 Da, calculated LogP ~7.3, polar surface area ~120 Angstrom2, suggesting low oral bioavailability (typical for PROTACs). No experimental PK data available. Based on analogous VHL-based PROTACs, plasma half-life (t½) after intravenous administration in mice is approximately 1-3 hours, clearance is moderate (10-30 mL/min/kg), and volume of distribution is high (>2 L/kg), indicating extensive tissue distribution. Oral bioavailability is typically <5%.
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| Toxicity/Toxicokinetics |
No formal toxicity studies have been conducted. As a research-grade PROTAC, potential toxicities include off-target degradation of other proteins containing similar recognition motifs, accumulation of the E3 ligase ligand (VHL ligand) fragment, and general cytotoxicity from prolonged ER degradation in non-target tissues. In vitro cytotoxicity assays (MTT) in MCF-7 cells show no significant cell death at degradation concentrations, but higher doses (>1 uM) may induce non-specific effects. No genotoxicity or cardiotoxicity data are available.
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| References | |
| Additional Infomation |
This compound is a research tool for studying ERalpha-targeted protein degradation in breast cancer models. It is not approved for clinical use and has not entered human trials. It serves as a lead for developing oral ER PROTACs. Additional information: the compound's structure comprises an ER antagonist (similar to raloxifene) linked to a VHL-recruiting moiety via a polyethylene glycol (PEG) linker. It is commercially available only for research purposes. Patent applications covering this series have been filed.
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| Molecular Formula |
C53H67F3N6O8S
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|---|---|
| Molecular Weight |
1005.19470334053
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| Exact Mass |
1004.469
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| CAS # |
2361114-15-8
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| PubChem CID |
138693144
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
7.3
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
22
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| Heavy Atom Count |
71
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| Complexity |
1720
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| Defined Atom Stereocenter Count |
6
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| SMILES |
S1C=NC(C)=C1C1C=CC(=CC=1)[C@H](C)NC([C@@H]1C[C@H](CN1C([C@H](C(C)(C)C)NC(COCCOCCOCCOC1C=C(C(=C(C=1)F)[C@@H]1C2=C(C3C=CC=CC=3N2)C[C@@H](C)N1CC(C)(C)F)F)=O)=O)O)=O
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| InChi Key |
WNWBHGDKGOSOKU-QIINAUKOSA-N
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| InChi Code |
InChI=1S/C53H67F3N6O8S/c1-31-23-39-38-11-9-10-12-42(38)59-46(39)47(62(31)29-53(7,8)56)45-40(54)25-37(26-41(45)55)70-22-21-68-18-17-67-19-20-69-28-44(64)60-49(52(4,5)6)51(66)61-27-36(63)24-43(61)50(65)58-32(2)34-13-15-35(16-14-34)48-33(3)57-30-71-48/h9-16,25-26,30-32,36,43,47,49,59,63H,17-24,27-29H2,1-8H3,(H,58,65)(H,60,64)/t31-,32+,36-,43+,47-,49-/m1/s1
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| Chemical Name |
(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
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. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~99.48 mM)
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|---|---|
| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.9948 mL | 4.9741 mL | 9.9483 mL | |
| 5 mM | 0.1990 mL | 0.9948 mL | 1.9897 mL | |
| 10 mM | 0.0995 mL | 0.4974 mL | 0.9948 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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