| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| Other Sizes |
| Targets |
ERα 0.053 nM (IC50)
GNE-149 is a potent antagonist of the Estrogen Receptor alpha (ERalpha), with an IC50 of 0.053 nM. It also functions as a selective estrogen receptor degrader (SERD), leading to the elimination of ERalpha protein. It is an orally bioavailable full antagonist with significant potency in higher species. |
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| ln Vitro |
GNE-149 showed antiproliferative action in MCF7 and T47D cells with IC50s of 0.66 and 0.69 nM, respectively[1].
GNE-149 shows potent antiproliferative action in MCF7 and T47D ER+ breast cancer cells with IC50s of 0.66 nM and 0.69 nM, respectively. As a full antagonist and SERD, it effectively degrades ERalpha protein and blocks estrogen-driven gene transcription and cell growth in vitro. |
| ln Vivo |
GNE-149 (0.3-30 mg/kg) demonstrates effectiveness in vivo in an MCF7 xenograft mouse model that harbors either an overexpressed Y537S mutant or wild-type (WT) ERα[1]. GNE-149 exhibits a good pharmacokinetic profile, with oral bioavailability (F; 31%, 49%, and 28% for Rat, Dog, and Cyno) and total clearance (CL; 19, 8, and 13 mL/min/kg for these three species)[1].
GNE-149 demonstrates effectiveness in vivo in an MCF7 xenograft mouse model that harbors either an overexpressed Y537S mutant (a common resistance mutation) or wild-type (WT) ERalpha. It demonstrates dose-dependent efficacy, with tumor regression observed at all doses above 0.3 mg/kg in the resistant Y537S mutant xenograft model. |
| Enzyme Assay |
Cell-free ERalpha binding assays are performed using a time-resolved fluorescence resonance energy transfer (TR-FRET) format. A GST-tagged ERalpha ligand-binding domain (LBD), a terbium-labeled anti-GST antibody, and a fluorescein-labeled coactivator peptide are used. The compound's ability to competitively displace an agonist is measured, and the IC50 is determined by the loss of TR-FRET signal.
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| Cell Assay |
ER+ breast cancer cell lines (e.g., MCF-7, T47D) are seeded in 96-well plates and treated with a dilution series of GNE-149 for 5-7 days. Cell viability is measured using the CellTiter-Glo luminescent cell viability assay to calculate the half-maximal inhibitory concentration (IC50) for growth inhibition. Additionally, ERalpha protein levels are assessed via Western blot to confirm target degradation.
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| Animal Protocol |
Animal/Disease Models: Female Crl:NU Foxn1 nu (nude) mice (at 7 weeks of age) bearing wild-type (WT) ERα or overexpressed Y537S mutant MCF7 tumor[1]
Doses: 0.3, 1, 3, 10, and 30 mg/kg Route of Administration: Orally qd for 21 days Experimental Results: demonstrated dose-dependent efficacy in the MCF7 WT and Y537S mutant xenograft model, with tumor regression observed at all doses above 0.3 mg/kg in Y537S mutant xenograft model. The in vivo efficacy of GNE-149 is evaluated in a xenograft mouse model. Female Crl:NU Foxn1nu (nude) mice bearing wild-type (WT) ERalpha or overexpressed Y537S mutant MCF7 tumors are treated with GNE-149 (0.3, 1, 3, 10, and 30 mg/kg) via oral gavage (qd) for 21 days. Tumor volumes are measured bi-weekly with calipers to assess dose-dependent tumor regression and growth inhibition. |
| ADME/Pharmacokinetics |
GNE-149 exhibits a good pharmacokinetic profile, with oral bioavailability (F) of 31%, 49%, and 28% for Rat, Dog, and Cynomolgus monkey, respectively. The total clearance (CL) in these species is 19, 8, and 13 mL/min/kg. This favorable PK supports once-daily oral dosing and robust target coverage in preclinical models.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies indicate that GNE-149 is well-tolerated at therapeutic doses. The primary observed effects are on-target pharmacodynamic effects related to ERalpha antagonism and degradation. No significant off-target toxicities have been reported, supporting its potential for further clinical development as a potent next-generation SERD.
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| References | |
| Additional Infomation |
GNE-149 is a next-generation, highly potent oral SERD. It is a research compound designed to overcome resistance mutations (like Y537S) that limit the efficacy of current endocrine therapies. Its superior in vitro and in vivo activity makes it a valuable tool for advancing the understanding of ER+ breast cancer therapy and a potential candidate for further clinical translation.
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| Molecular Formula |
C28H33F4N3O
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|---|---|
| Molecular Weight |
503.574741125107
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| Exact Mass |
503.255
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| CAS # |
1953132-75-6
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| PubChem CID |
121410669
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| Appearance |
White to light yellow solid powder
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| LogP |
5.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
36
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| Complexity |
726
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| Defined Atom Stereocenter Count |
2
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| SMILES |
N1C2=C(C=CC=C2)C2C[C@@H](C)N(CC(F)(C)C)[C@H](C3=C(F)C=C(OC4CN(CCCF)C4)C=C3F)C1=2
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| InChi Key |
BKHIBYHLBQEIQK-XGCWNURASA-N
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| InChi Code |
InChI=1S/C28H33F4N3O/c1-17-11-21-20-7-4-5-8-24(20)33-26(21)27(35(17)16-28(2,3)32)25-22(30)12-18(13-23(25)31)36-19-14-34(15-19)10-6-9-29/h4-5,7-8,12-13,17,19,27,33H,6,9-11,14-16H2,1-3H3/t17-,27-/m1/s1
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| Chemical Name |
(1R,3R)-1-[2,6-difluoro-4-[1-(3-fluoropropyl)azetidin-3-yl]oxyphenyl]-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole
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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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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: 50 mg/mL (99.29 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9858 mL | 9.9291 mL | 19.8582 mL | |
| 5 mM | 0.3972 mL | 1.9858 mL | 3.9716 mL | |
| 10 mM | 0.1986 mL | 0.9929 mL | 1.9858 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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