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Amcenestrant (SAR-439859; SAR439859) is a potent, orally available, and nonsteroidal estrogen receptor degrader (SERD) with potential anticancer activity. It degrades ER with an EC50 of 0.2 nM for ERα degradation.
| Targets |
ERα(EC50 = 0.2 nM)
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|---|---|
| ln Vitro |
SAR439859 (compound 43d) exhibits the strongest in vivo anticancer activity against a variety of BC cell lines and patient-derived xenografts, including those with ERα mutations [1].
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| ln Vivo |
At a dose of 25 mg/kg/BID, SAR439859 (Compound 43d; Valve; 2.5–25 mg/kg; twice daily for 30 days) showed a significant reduction in tumor growth [1]. In the largest animal species tested, 3 mg/kg, minimum 10 mg/kg) shows low to moderate clearance (0.03-1.92 L/h?kg), low to moderate volume of distribution (Vss=0.5-6.1 L/kg), and good cross-species bioavailability (54-76%). Be aware that the T1/2 time varies depending on the species: 1.98 hours for mice, 4.13 hours for fish, and 9.80 hours for dogs, for example [1].
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| Enzyme Assay |
Determination of ERα Crystal Structure[1]
The ERα ligand-binding-domain (LBD)-mutated (amino acids 298–554) Tyr-536-Ser was induced in BL21 (DE3) cells and purified. The purified protein was then concentrated to ∼12 mg/mL in 50 mM Tris, pH 8, 150 mM NaCl, 50 mM β-mercapto-ethanol, 10% glycerol. The protein was incubated with the compound at 1 mM overnight at 4 °C. The protein with compound was crystallized by the hanging drop vapor diffusion method at 20 °C with a 1:1 ratio of protein solution to reservoir solution of 22.5% PEG-4000, 100 mM Cacodylate Na pH 6.5, and 0.2 M MgCl2 with 0.2 μL of the diluted seeding solution. The crystals were cryoprotected in glycerol to the mother liquor. Crystals were flash-frozen in liquid nitrogen prior to data collection. Diffraction data were collected at the SOLEIL synchrotron facility, Beamline Proxima 1, Saclay, France and were processed with programs AutoPROC and STARANISO (Global Phasing) The structure was solved using molecular replacement technique with coordinates of ER-LBD available internally and the program PHASER. The structure was refined using REFINE (Global Phasing) (X), the ligand was placed manually, and the manual rebuilds were made in COOT. The final validation checks were performed using MOLPROBITY prior to the deposition of coordinates and structure factors into the Protein Data Bank. The data set statistics of crystal structure are given in Table 8. |
| Cell Assay |
Estrogen Receptor Degradation Activity[1]
The measurements on the protein abundance of ER were made by fluorescence detection in the MCF7 BC cell line. MCF7 cells (ATCC) were seeded in a 384-well microplate at a concentration of 10 000 cells/30 μL per well in red-phenol-free MEM alpha medium containing 5% charcoal-dextran-stripped fetal bovine serum (FBS). The following day, compounds were added to the cells in a 10-point dose response with a 1:3 fold serial dilution in 2.5 μL at final concentrations ranging from 300 to 0.15 nM or 0.1 μM for fulvestrant (used as a positive control). At 4 h post-compound-addition, the cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.05% triton) for 15 min at room temperature and then washed twice with PBS-1×. Then, cells were incubated overnight in a cold room with 25 μL of anti-ER rabbit monoclonal antibody diluted at 1:500 in Power Block buffer. Wells were washed three times with PBS-1× and incubated at 37 °C for 60 min in Power Block buffer containing goat antirabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (1.5 μM final concentration). Cells were then washed three times in PBS-1× and scanned in an ACUMEN explorer apparatus. Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ERα and DNA, respectively. The degradation potency is determined as the concentration of compound that achieves 50% degradation of the estrogen receptor (or IC50) in nanomoles. The percent ERα level decrease was calculated as follows: % inhibition = 100*(1 – (sample – fulvestrant)/(DMSO – fulvestrant)). |
| Animal Protocol |
Animal/Disease Models: Nu/nu mouse MCF7 tumor xenograft model [1]
Doses: 2.5, 5, 12.5, 25 mg/kg Doses: Oral;. twice (two times) daily for 30 days Experimental Results: Demonstrated significant tumor growth inhibition and demonstrated tumor regression at a dose of 25 mg/kg/BID. Animal/Disease Models: Mice, rats and dogs [1] Doses: 3 mg/kg (iv) and 10 mg/kg (oral) (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)or oral Experimental Results: In three Shows low to moderate clearance among animal species tested (0.03-1.92 L/h·kg), low to moderate volume of distribution (Vss=0.5-6.1 L/kg), and good bioavailability across species degree (54-76%). MCF-7 Xenograft Studies[1] 0.72 mg of 17-β estradiol pellets (90 days release) was subcutaneously implanted into nu/nu mice 2 days prior to MCF7 cell implantation. MCF7 cells were grown in Eagle’s minimum essential medium supplemented with 10% FBS and 0.01 mg/mL human insulin in 5% CO2 at 37 °C. The cells were harvested and resuspended in DPBS with 50% matrigel and subcutaneously implanted into the right flank of female nude mice. The tumor volume (length × width2/2) was monitored biweekly. When tumors reached an average volume of 200 mm3, animals were randomized and treatment was started. Animals were treated with the vehicle or the 43d compound twice daily. The tumor volume and body weight were monitored biweekly throughout the study. |
| References |
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| Additional Infomation |
Amcenestrant is an orally available, nonsteroidal selective estrogen receptor degrader/downregulator (SERD), with potential antineoplastic activity. Upon oral administration, amcenestrant specifically targets and binds to the estrogen receptor (ER) and induces a conformational change that promotes ER degradation. This prevents ER-mediated signaling and inhibits both the growth and survival of ER-expressing cancer cells.
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| Molecular Formula |
C₃₁H₃₀CL₂FNO₃
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|---|---|
| Molecular Weight |
554.48
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| Exact Mass |
553.16
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| Elemental Analysis |
C, 67.15; H, 5.45; Cl, 12.79; F, 3.43; N, 2.53; O, 8.66
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| CAS # |
2114339-57-8
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| PubChem CID |
130232326
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| Appearance |
White to off-white solid powder
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| Density |
1.297±0.06 g/cm3(Predicted)
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| Boiling Point |
676.7±55.0 °C(Predicted)
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
38
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| Complexity |
832
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C([H])=C(C([H])=C([H])C=1C1C([H])([H])C([H])([H])C([H])([H])C2C([H])=C(C(=O)O[H])C([H])=C([H])C=2C=1C1C([H])=C([H])C(=C([H])C=1[H])O[C@@]1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])F)C1([H])[H])Cl
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| InChi Key |
KISZAGQTIXIVAR-VWLOTQADSA-N
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| InChi Code |
InChI=1S/C31H30Cl2FNO3/c32-23-8-12-27(29(33)18-23)28-4-1-3-21-17-22(31(36)37)7-11-26(21)30(28)20-5-9-24(10-6-20)38-25-13-16-35(19-25)15-2-14-34/h5-12,17-18,25H,1-4,13-16,19H2,(H,36,37)/t25-/m0/s1
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| Chemical Name |
6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
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| Synonyms |
SAR439859; SAR439859; Amcenestrant [INN]; Amcenestrant [USAN]; TBF1NHY02O; (S)-8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid; SAR-439859
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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 |
| 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 : ~83.33 mg/mL (~150.28 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 8.33 mg/mL (15.02 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 83.3 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. Solubility in Formulation 2: ≥ 8.33 mg/mL (15.02 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 83.3 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. View More
Solubility in Formulation 3: ≥ 8.33 mg/mL (15.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8035 mL | 9.0175 mL | 18.0349 mL | |
| 5 mM | 0.3607 mL | 1.8035 mL | 3.6070 mL | |
| 10 mM | 0.1803 mL | 0.9017 mL | 1.8035 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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