| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg | |||
| Other Sizes |
Purity: ≥98%
| Targets |
Estrogen receptor α (ERα), both wild-type and mutant forms.
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| ln Vitro |
In biochemical and cell-based experiments, H3B-6545 is a highly selective small molecule that effectively opposes both wild-type and mutant ERα. Under continuous as well as washout treatment circumstances, higher cell potency of H3B-6545 is confirmed in vitro by comparisons with standard of care and other experimental agents[1]. H3B-6545, a member of a new class of ERα antagonists known as selective ER covalent antagonist (SERCA), targets C530 and imposes a distinct antagonist conformation to inactivate both wild-type and mutant ERα. A first-in-class selective ER covalent antagonist (SERCA) is H3B -6545. H3B-6545 suppresses the development of ERαWT-positive breast cancer cells and ERαWT activity. H3B-6545 effectively decreases ERαWT activity and ERαWT-positive breast cancer lines' growth. GI50s for MCF7, HCC1428, BT483, T47D, and CAMA-1 cell lines were 0.3-0.4, 1.0, 0.5, 5.2, and 0.2 nM, respectively[1].
H3B-6545 inhibits ERαWT activity and suppresses the growth of ERαWT-positive breast cancer cell lines. It is a covalent antagonist that binds irreversibly to ERα, providing sustained target engagement. The compound shows improved activity over standard-of-care therapies in preclinical models. It inhibits both wild-type and mutant ERα, making it effective against endocrine-resistant breast cancer. |
| ln Vivo |
In the MCF-7 xenograft model, oral H3B-6545 given once daily exhibits strong activity and superior efficacy to fulvestrant, with maximal anticancer activity at doses >10x below the maximum tolerated dose in mice. H3B-6545 is also well tolerated over a wide dose range and at exposures that significantly exceed those required for efficacy in mouse xenograft models. Furthermore, in patient-derived xenograft models of estrogen receptor positive breast cancer, including models carrying ERα mutations in rats and monkeys, H3B-6545 exhibits superior antitumor activity compared to Tamoxifen and Fulvestrant[1].
In vivo, H3B-6545 has demonstrated efficacy in xenograft models of ER-positive breast cancer, including models with ESR1 mutations that confer resistance to standard endocrine therapies. The compound is orally bioavailable and shows potent antitumor activity. Specific dosing regimens and detailed efficacy data are available from preclinical and early clinical studies. |
| Enzyme Assay |
ERα binding is assessed using in vitro radioligand binding assays with recombinant ERα protein. Covalent binding is confirmed by washout experiments or mass spectrometry. Antagonist activity is evaluated using reporter gene assays in ER-responsive cells. Selectivity over other nuclear receptors is confirmed by profiling. IC50 values are calculated from dose-response curves.
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| Cell Assay |
Cellular activity is evaluated in ERα-positive breast cancer cell lines such as MCF-7 and T47D, including those with ESR1 mutations. Cells are treated with H3B-6545 at various concentrations and cell proliferation is measured by MTT or colony formation assays. ERα target gene expression (e.g., GREB1, PGR) is measured by qRT-PCR. ERα protein levels and phosphorylation are assessed by Western blot.
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| Animal Protocol |
In vivo efficacy is studied in mouse xenograft models of ER-positive breast cancer, including patient-derived xenografts (PDX) and models with ESR1 mutations. H3B-6545 is administered orally at various doses. Tumor growth is measured over time. Pharmacodynamic markers including ERα target gene expression and ERα occupancy in tumor tissue are assessed.
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| ADME/Pharmacokinetics |
H3B-6545 is orally bioavailable with good pharmacokinetic properties. It is a small molecule with a molecular weight of approximately 460 g/mol. Detailed pharmacokinetic parameters including half-life, Cmax, AUC, and oral bioavailability are available from preclinical and clinical studies. The compound is formulated for oral administration.
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| Toxicity/Toxicokinetics |
Safety data from preclinical studies indicate H3B-6545 is generally well-tolerated at therapeutic doses. As an estrogen receptor antagonist, potential side effects may include those associated with endocrine therapies such as hot flashes and joint pain. Full toxicological profiles are available from preclinical and clinical study reports. The compound is for research use only.
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| References |
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| Additional Infomation |
H3B-6545, a selective estrogen receptor covalent antagonist, is an orally potent selective estrogen receptor α (ERα; ERa; ESR1; nuclear receptor subfamily 3, group A, member 1; NR3A1) covalent antagonist with potential antitumor activity. After oral administration, the selective estrogen receptor covalent antagonist (SERCA) H3B-6545 selectively covalently binds to a cysteine residue specific to ERα (this residue is not present in other nuclear hormone receptors), thereby inhibiting ERα activity. This inhibits the growth and survival of cancer cells expressing ERα. ERα is a nuclear hormone receptor that is frequently overexpressed and/or mutated in various cancer cell types. It plays a crucial role in the proliferation and survival of tumor cells.
H3B-6545 is a first-in-class selective ER covalent antagonist (SERCA) developed for the treatment of metastatic ER-positive, HER2-negative breast cancer. It has been investigated in clinical trials for patients with endocrine-resistant breast cancer. The compound represents a novel therapeutic approach by covalently binding to ERα, providing sustained target inhibition and overcoming resistance mutations. |
| Molecular Formula |
C30H29F4N5O2
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|---|---|
| Molecular Weight |
567.5772
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| Exact Mass |
567.225
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| CAS # |
2052130-80-8
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| Related CAS # |
H3B-6545 hydrochloride;2052132-51-9
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| PubChem CID |
124091040
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
6.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
41
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| Complexity |
906
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C([H])([H])/C(/C1C([H])=C([H])C([H])=C([H])C=1[H])=C(/C1=C([H])N=C(C([H])=C1[H])OC([H])([H])C([H])([H])N([H])C([H])([H])/C(/[H])=C(\[H])/C(N(C([H])([H])[H])C([H])([H])[H])=O)\C1C([H])=C([H])C2C(=C(N([H])N=2)F)C=1[H])(F)F
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| InChi Key |
JPFTZIJTXCHJNE-HMOQVRKWSA-N
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| InChi Code |
InChI=1S/C30H29F4N5O2/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)/b9-6+,28-24-
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| Chemical Name |
(E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide
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| Synonyms |
H3B-6545 H3B 6545 H3B6545
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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 : ~100 mg/mL (~176.19 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.66 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 (3.66 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7619 mL | 8.8093 mL | 17.6187 mL | |
| 5 mM | 0.3524 mL | 1.7619 mL | 3.5237 mL | |
| 10 mM | 0.1762 mL | 0.8809 mL | 1.7619 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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