| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 100mg | |||
| Other Sizes |
| Targets |
H3B-6545 Hydrochloride targets estrogen receptor alpha (ERalpha; ESR1; nuclear receptor subfamily 3, group A, member 1; NR3A1). As a selective estrogen receptor covalent antagonist (SERCA), the compound forms a covalent bond with ERalpha, leading to irreversible inactivation of the receptor. H3B-6545 potently antagonizes both wild-type and mutant ERalpha. By covalently binding to and inactivating ERalpha, the compound blocks estrogen-mediated signaling, which is a key driver of tumor growth in ER-positive breast cancer.
|
|---|---|
| ln Vitro |
In biochemical and cellular experiments, H3B-6545 is a highly selective small molecule that efficiently opposes both wild-type and mutant ERα. Increased cellular potency of H3B-6545 under continuous and washout treatment settings was validated by in vitro comparisons with standard care and other experimental reagents [1]. H3B-6545 belongs to a new class of ERα antagonists called selective ER covalent antagonists (SERCA), which bind C530 and force an antagonistic conformation that inactivates both wild-type and mutant ERα. A first-class selective ER covalent antagonist (SERCA) is H3B-6545. H3B-6545 suppresses the development of ERαWT-positive breast cancer cell lines and ERαWT activity. H3B-6545 is an efficient inhibitor of ERαWT activity that also prevents ERαWT-positive breast cancer cell lines from proliferating. The GI50s of the following cell lines: MCF7, HCC1428, BT483, T47D, and CAMA-1 are 0.3-0.4, 1.0, 0.5, 5.2, and 0.2 nM [1].
In vitro, H3B-6545 Hydrochloride acts as a potent antagonist of estrogen receptor alpha (ERalpha). The compound inactivates both wild-type and mutant ERalpha through covalent binding. H3B-6545 is a highly selective small molecule that potently antagonizes ERalpha signaling. These in vitro properties establish H3B-6545 Hydrochloride as a valuable research tool for studying ERalpha biology and for evaluating therapeutic strategies for ER-positive breast cancer, including tumors with ERalpha mutations. |
| ln Vivo |
Using the MCF-7 xenograft model, once-daily oral administration of H3B-6545 showed better activity and efficacy than fulvestrant in vivo. The peak antitumor efficacy was reached at a dose that was ten times lower than the highest dose that mice could tolerate. H3B-6545 additionally shown enhanced anti-tumor effectiveness against fulvestrant and tamoxifen in patient-derived xenograft models of estrogen receptor-positive breast cancer, including those with ERα mutations in rats and monkeys. H3B-6545's oncological action was well tolerated over a wide range of exposure and doses. greatly beyond the quantity needed in mouse xenograft models in order to be effective [1].
In vivo, H3B-6545 Hydrochloride has been shown to prevent bone loss in ovariectomized Sprague-Dawley rats. The compound is being researched for the treatment of metastatic ER-positive, HER2-negative breast cancer. As an orally bioavailable SERCA, H3B-6545 Hydrochloride offers the potential for convenient oral administration in therapeutic settings. Its ability to inactivate both wild-type and mutant ERalpha makes it a promising candidate for overcoming resistance to standard endocrine therapies. |
| Enzyme Assay |
Receptor binding assays for H3B-6545 Hydrochloride are performed using purified recombinant estrogen receptor alpha (ERalpha) protein or using cell-based competition binding assays. Binding affinity and covalent modification of ERalpha are assessed using methods such as fluorescence polarization, surface plasmon resonance (SPR), or mass spectrometry. H3B-6545 Hydrochloride is incubated with ERalpha at varying concentrations, and the extent of covalent binding is determined. Competition binding experiments with labeled estradiol may be conducted to assess the compound's ability to displace the natural ligand.
|
| Cell Assay |
Cellular assays for H3B-6545 Hydrochloride are performed using ER-positive breast cancer cell lines, including those expressing wild-type or mutant ERalpha. Cells are cultured in appropriate media and treated with H3B-6545 Hydrochloride at varying concentrations for defined time periods. Cell viability and proliferation are assessed using standard assays such as MTT, CellTiter-Glo, or colony formation assays. ERalpha signaling is assessed by measuring the expression of estrogen-responsive genes by qRT-PCR and by assessing ERalpha protein levels and covalent modification by Western blot.
|
| Animal Protocol |
In vivo studies with H3B-6545 Hydrochloride are conducted in mouse xenograft models using ER-positive breast cancer cell lines. H3B-6545 Hydrochloride is administered via oral routes at defined doses and schedules. Tumor growth is monitored by caliper measurements, and tumor volumes are calculated. Bone loss prevention studies are conducted in ovariectomized rats. Pharmacokinetic parameters are determined from plasma samples collected at various time points. The compound's efficacy and safety are being evaluated in preclinical models.
|
| ADME/Pharmacokinetics |
H3B-6545 Hydrochloride has a molecular formula of C27H29ClF3N3O4 and a molecular weight of 552.0. The compound is orally bioavailable. Detailed pharmacokinetic parameters, including oral bioavailability and half-life, have been characterized in preclinical studies. The compound is soluble in DMSO. It should be stored at -20degC for long-term stability. H3B-6545 Hydrochloride is intended for research use only and is not approved for clinical use.
|
| Toxicity/Toxicokinetics |
H3B-6545 Hydrochloride has been evaluated in preclinical studies for safety and efficacy. The compound is intended for research use only and is not approved for human therapeutic applications. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and adherence to institutional biosafety and chemical hygiene guidelines. The compound has a purity of ≥98%.
|
| References |
|
| Additional Infomation |
H3B-6545 Hydrochloride is a first-in-class, orally bioavailable Selective Estrogen Receptor Covalent Antagonist (SERCA) designed to inactivate both wild-type and mutant estrogen receptor alpha (ERalpha). It is indicated for the research of metastatic ER-positive, HER2-negative breast cancer and has been shown to prevent bone loss in ovariectomized rats. H3B-6545 Hydrochloride is for research purposes only and is not approved for clinical use.
|
| Molecular Formula |
C30H30CLF4N5O2
|
|---|---|
| Molecular Weight |
604.038119792938
|
| Exact Mass |
603.202
|
| CAS # |
2052132-51-9
|
| Related CAS # |
H3B-6545;2052130-80-8
|
| PubChem CID |
124091099
|
| Appearance |
White to yellow solid powder
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
42
|
| Complexity |
906
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
Cl.FC(C/C(/C1C=CC=CC=1)=C(/C1C=NC(=CC=1)OCCNC/C=C/C(N(C)C)=O)\C1C=CC2C(=C(NN=2)F)C=1)(F)F
|
| InChi Key |
KNSVJVMDHBDKJL-XVBKFJSKSA-N
|
| InChi Code |
InChI=1S/C30H29F4N5O2.ClH/c1-39(2)27(40)9-6-14-35-15-16-41-26-13-11-22(19-36-26)28(21-10-12-25-23(17-21)29(31)38-37-25)24(18-30(32,33)34)20-7-4-3-5-8-20;/h3-13,17,19,35H,14-16,18H2,1-2H3,(H,37,38);1H/b9-6+,28-24-;
|
| Chemical Name |
(E)-N,N-dimethyl-4-[2-[5-[(Z)-4,4,4-trifluoro-1-(3-fluoro-2H-indazol-5-yl)-2-phenylbut-1-enyl]pyridin-2-yl]oxyethylamino]but-2-enamide;hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| 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, 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)
|
| Solubility (In Vitro) |
DMSO : ~83.33 mg/mL (~137.95 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.44 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 20.8 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: ≥ 2.08 mg/mL (3.44 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 20.8 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: ≥ 2.08 mg/mL (3.44 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 | 1.6555 mL | 8.2776 mL | 16.5552 mL | |
| 5 mM | 0.3311 mL | 1.6555 mL | 3.3110 mL | |
| 10 mM | 0.1656 mL | 0.8278 mL | 1.6555 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
