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.
Physicochemical Properties
| 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) |
Biological Activity
| 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]. |
| 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]. |
| 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 |
[1]. Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer. Cancer Discov. 2018 Sep;8(9):1176-1193. |
Solubility Data
| 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 |