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H3B-5942 (H3B5942) is a selective, irreversible (covalent) and orally bioavailable estrogen receptor antagonist with antitumor activity (better than fulvestrant). Acts by inactivating both wild-type and mutant ERα by targeting Cys530, with Kis of 1 nM and 0.41 nM, respectively. H3B-5942 reduces ERα target gene GREB1, shows potent antitumor activity both in multiple cell lines or animals bearing ERαWT or ERα mutations.
| Targets |
Estrogen receptor alpha (ERα) wild-type (ERα^{WT})
Estrogen receptor alpha (ERα) mutant (ERα^{MUT})[1] |
|---|---|
| ln Vitro |
H3B-5942 is an estrogen receptor covalent antagonist that is selective and irreversible. It works by targeting Cys530 to inactivate both wild-type and mutant ERα, with Kis values of 1 nM and 0.41 nM, respectively [1]. In contrast to SERM/SERD, H3B-5942 has the ability to raise ERα protein levels and inhibit ERα-dependent transcription in breast cancer cells. The ERα target gene GREB1 is reduced by H3B-5942 (0.01-10 μM) in the PDX-ERαY537S/WT line, several MCF7-ERαMUT lines, and MCF7-ERαWT [1]. With GI50 values of 0.5, 2, and 30 nM, respectively, H3B-5942 also inhibited the proliferation of MCF7-Parental, MCF7-LTED-ERαWT, and MCF7-LTED-ERαY537C lines. In a range of cell lines carrying ERαWT or clinically prevalent ERα mutations, H3B-5942 (10–25 nM) exhibits synergistic inhibitory effects when combined with CDK4/6 inhibitors (≥25 pM) [1].
H3B-5942 exhibits enhanced antagonist activity across a panel of ERα^{WT} and ERα^{MUT} tumor cell lines when compared with standard-of-care and experimental agents[1] The potency of H3B-5942 can be further improved in combination with CDK4/6 inhibitors or mTOR inhibitors in both ERα^{WT} and ERα^{MUT} cell lines[1] |
| ln Vivo |
In the athymic female nude mouse MCF7 xenograft model, H3B-5942 (1, 3, 10, or 30 mg/kg orally once daily for 17 days) dose-dependently suppresses tumor growth [1]. H3B-5942 (3, 10, 30, 100, and 200 mg/kg, orally, once daily) demonstrated comparable anti-tumor efficacy in the athymic female nude mouse model of the ERαY537S/WT ST941 [1].
H3B-5942 demonstrates significant single-agent antitumor activity in xenograft models representing ERα^{WT} and ERα^{Y537S} (a type of ERα^{MUT}) breast cancer[1] The in vivo antitumor efficacy of H3B-5942 is superior to that of fulvestrant in the aforementioned xenograft models[1] |
| Animal Protocol |
Animal/Disease Models: Athymic female nude mouse MCF7 xenograft model [1]
Doses: 1, 3, 10 or 30 mg/kg Route of Administration: Orally, one time/day (qd×1) for 17 days Experimental Results: Demonstrated tumor growth Inhibition (TGI) on day 17 were 19%, 41%, 68% and 83% respectively. |
| References | |
| Additional Infomation |
H3B-5942 belongs to the class of selective estrogen receptor covalent antagonists (SERCA) [1]
H3B-5942 covalently inactivates ERαWT and ERαMUT by targeting Cys530, and endows them with a unique antagonist conformation [1] H3B-5942 is orally available [1] H3B-5942 is designed to treat ERαWT and ERαMUT breast cancer to meet the unmet needs of endocrine therapy-resistant breast cancer patients (up to 30% of such patients carry ERα mutations that confer resistance) [1] |
| Molecular Formula |
C31H34N4O2
|
|---|---|
| Molecular Weight |
494.627267360687
|
| Exact Mass |
494.27
|
| Elemental Analysis |
C, 75.28; H, 6.93; N, 11.33; O, 6.47
|
| CAS # |
2052128-15-9
|
| Related CAS # |
2052132-46-2 (HCl);2052128-15-9;
|
| PubChem CID |
124091011
|
| Appearance |
White to off-white solid powder
|
| LogP |
6.1
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
37
|
| Complexity |
765
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC/C(=C(/C1=CC=C(C=C1)OCCNC/C=C/C(=O)N(C)C)\C2=CC3=C(C=C2)NN=C3)/C4=CC=CC=C4
|
| InChi Key |
BYAUIDXIQATDBT-GIHLFXONSA-N
|
| InChi Code |
InChI=1S/C31H34N4O2/c1-4-28(23-9-6-5-7-10-23)31(25-14-17-29-26(21-25)22-33-34-29)24-12-15-27(16-13-24)37-20-19-32-18-8-11-30(36)35(2)3/h5-17,21-22,32H,4,18-20H2,1-3H3,(H,33,34)/b11-8+,31-28+
|
| Chemical Name |
(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide
|
| Synonyms |
H3B-5942 H3B 5942 H3B5942
|
| 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 |
| 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 (~168.47 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.21 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 (4.21 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 | 2.0217 mL | 10.1086 mL | 20.2171 mL | |
| 5 mM | 0.4043 mL | 2.0217 mL | 4.0434 mL | |
| 10 mM | 0.2022 mL | 1.0109 mL | 2.0217 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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