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Purity: ≥98%
H3B-6545 (H3B 6545; H3B6545) is a novel, potent, orally bioavailable and selective small molecule modulator of wild-type and mutant Estrogen Receptor (ERα), also called estrogen receptor covalent antagonist (SERCA). Preclinical data indicates H3B-6545 inhibits the growth of cell line and patient-derived xenograft models of wild-type and mutant ERα with improved activity over standard-of-care therapies.
| 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].
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| 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].
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| References |
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| Additional Infomation |
Selective Estrogen Receptor Covalent Antagonist H3B-6545 is an orally available, selective and covalent antagonist of estrogen receptor alpha (ERalpha; ERa; ESR1; nuclear receptor subfamily 3, group A, member 1; NR3A1), with potential antineoplastic activity. Upon oral administration, selective estrogen receptor covalent antagonist (SERCA) H3B-6545 selectively and covalently binds to a cysteine that is unique to ERalpha and is not present in other nuclear hormone receptors, thereby inhibiting the activity of ERalpha. This inhibits the growth and survival of ERalpha-expressing cancer cells. ERalpha, a nuclear hormone receptor, is often overexpressed and/or mutated in a variety of cancer cell types. It plays a key role in tumor cell proliferation and survival.
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| 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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