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Purity: ≥98%
Brilanestrant (formerly known as GDC-0810, ARN-810 and/or RG6046) is a novel, potent and orally bioavailable Selective Estrogen Receptor Degrader (SERD) that is presently being studied in clinical trials for women with locally advanced or metastatic estrogen receptor-positive breast cancer.It has shown strong activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer.xenografts of breast cancer resistant to tamoxifen. In contrast to tamoxifen and other ER therapies, GDC-0810 induces a different ERα conformation and does not cause ER agonism in MCF7 cells similar to that of tamoxifen.
| Targets |
estrogen receptor (IC50 = 0.7 nM)
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| ln Vitro |
GDC-0810 demonstrates a low nanomolar affinity for binding both ERα and ERβ in cell-free radio-ligand competitive binding assays [2]. GDC-0810 exhibits little to no inhibition (IC50 > 20 μM) against CYP1A2, CYP2D6, or CYP3A4. It also has a modest inhibitory effect (IC50 = 2.2 and 3.3 μM, respectively) on CYP2C9 and CYP2C19, and a strong inhibition (IC50 of <0.1 μM) on CYP2C8. It is also discovered that GDC-0810 exhibits good selectivity over other nuclear hormone receptors. GDC-0810 shows negligible activity (IC50 > 1 μM) in transcriptional reporter assays for the mineralocorticoid (MR), progesterone-A (PR-A), progesterone (PR-B), and glucocorticoid (GR) receptors. GDC-0810 shows little activity toward the GR (IC50 = 0.99 μM) and androgen receptor (AR; IC50 > 4 μM) in binding assays[1]. GDC-0810 requires the 26S proteasome in order to deplete ERα. Both in vitro and in vivo, GDC-0810 opposes mutants of the ERα ligand binding domain. Although GDC-0810 has a slightly higher IC50 (WT: 2.6 nM vs. ER.Y537S: 5.5 nM and ER.D538G: 5.4 nM), it still has the ability to potently displace E2 from the ligand binding domain in cell-free E2 competitive binding assays used to determine the binding of GDC-0810 to ER.WT, ER.Y537S, and ER.D538G ligand binding domains. Although it has a ~five-seven fold lower biochemical potency than wild-type ER, GDC-0810 can compete the PGC1α co-activator peptide off the mutated ligand binding domain, suggesting that GDC-0810 can drive a conformational shift of mutant ER from "active" to "inactive"[2].
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| ln Vivo |
GDC-0810 has a good bioavailability (40–60%) and a low clearance molecule across species, according to its pharmacokinetic profile. The compound has a low to moderate volume of distribution (Vss = 0.2−2.0 L/kg across species) and is highly bound to plasma proteins (>99.5% across species), as would be expected for a lipophilic carboxylic acid. In xenograft models of breast cancer that are both tamoxifen-sensitive and tamoxifen-resistant, GDC-0810 shows strong activity and good bioavailability across species[1]. In both vitro and in vivo uterine models, GDC-0810 exhibits modest estrogenic activity[2].
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| Enzyme Assay |
GDC-0810 is a potent ER-α binder (IC50=6.1 nM), a full transcriptional antagonist with no agonism (3× ERE, IC50=2 nM), and displays good potency and efficacy in ER-α degradation (EC50=0.7 nM) and MCF-7 breast cancer cell viability (IC50=2.5 nM) assays.
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| Cell Assay |
MCF-7 cells are cultured in RPMI with 10% FBS and 20 mM HEPES at a concentration of 40000 cells per milliliter. Next, a 384-well plate is filled with 16 μL of the cell suspension, containing 640 cells, and the cells are incubated for an entire night to promote cell adhesion. The next day, each compound is added to the cells in 16 μL at a final concentration ranging from 10 to 0.000005 μM through a 10-point, serial 1:5 dilution. Following five days of compound exposure, the cells are treated with 16 μL of CellTiter-GLo, and the relative luminescence units of each well are ascertained. To obtain a background value, 32 μL of medium without cells is mixed with CellTiter-GLo. The following formula is used to calculate each sample's percent viability: (RLU sample-RLU background ×100=%viability; RLU untreated cells-RLU background).
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| Animal Protocol |
Subcutaneous implants of time-release pellets containing 0.72 mg 17-β estradiol are made in nu/nu mice. MCF-7 cells are cultured at 37°C with 5% CO2 in RPMI supplemented with 10% FBS. Trypsinized cells are separated and then resuspended at a density of 1×107 cells/mL in 50% RPMI serum-free and 50% Matrigel. Two to three days after pellet implantation, MCF-7 cells are subcutaneously injected (100 μL/animal) into the right flank. Every two weeks, the tumor volume (length × width/2) is measured. When tumors get to about 200 mm3 on average, treatment is initiated and the animals are randomized. For four weeks, animals are given daily treatments with a vehicle or compound. Throughout the trial, tumor volume and body weight are recorded every two weeks.
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| References |
| Molecular Formula |
C26H20CLFN2O2
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| Molecular Weight |
446.9
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| Exact Mass |
446.12
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| Elemental Analysis |
C, 69.88; H, 4.51; Cl, 7.93; F, 4.25; N, 6.27; O, 7.16
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| CAS # |
1365888-06-7
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CC/C(=C(/C1=CC=C(C=C1)/C=C/C(=O)O)\C2=CC3=C(C=C2)NN=C3)/C4=C(C=C(C=C4)F)Cl
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| InChi Key |
BURHGPHDEVGCEZ-KJGLQBJMSA-N
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| InChi Code |
InChI=1S/C26H20ClFN2O2/c1-2-21(22-10-9-20(28)14-23(22)27)26(18-8-11-24-19(13-18)15-29-30-24)17-6-3-16(4-7-17)5-12-25(31)32/h3-15H,2H2,1H3,(H,29,30)(H,31,32)/b12-5+,26-21+
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| Chemical Name |
(E)-3-[4-[(E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-enyl]phenyl]prop-2-enoic acid
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.59 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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.59 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. View More
Solubility in Formulation 3: 2.08 mg/mL (4.65 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2376 mL | 11.1882 mL | 22.3764 mL | |
| 5 mM | 0.4475 mL | 2.2376 mL | 4.4753 mL | |
| 10 mM | 0.2238 mL | 1.1188 mL | 2.2376 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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