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| Targets |
Rintodestrant targets the estrogen receptor (ER), functioning as a selective estrogen receptor degrader (SERD). It acts as an antagonist by binding to ER, inducing receptor conformational changes that lead to its ubiquitination and proteasomal degradation, thereby reducing ER signaling in breast cancer cells.
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| ln Vitro |
Rintodestrant (G1T48), like pure antiestrogen fulvestrant, is a strong and effective inhibitor of estrogen-mediated transcription and proliferation in ER-positive breast cancer cells[1]. Only ER-positive breast cancer cells are preferentially inhibited in their proliferation by rindodestrant (G1T48)[1].
In vitro, Rintodestrant potently inhibits ER+ breast cancer cell proliferation (e.g., MCF-7 cells) with IC50 values in the low nanomolar range. It effectively degrades ER protein and downregulates ER target gene expression, including those mediated by the constitutively active ESR1 mutation Y537S. |
| ln Vivo |
In endocrine-resistant breast cancer models, rimodestrant (G1T48, 30 or 100 mg/kg) blocks estrogen signaling[1].
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| Enzyme Assay |
A competitive radioligand binding assay using purified estrogen receptor (ER) protein and [3H]-estradiol can measure Rintodestrant binding affinity. Increasing concentrations of Rintodestrant (0.1 nM-10 uM) are incubated with ER (1-5 nM) and [3H]-estradiol (1 nM) in binding buffer for 2-4 h at 4degC, followed by charcoal-dextran separation and liquid scintillation counting.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: MCF7 cells. Tested Concentrations: 1 pM-1 μM. Incubation Duration: 18 h. Experimental Results: Downregulates the estrogen receptor in breast cancer cells. Dramatically inhibited estrogen-mediated growth of MCF7 cells demonstrating approximately threefold higher potency when compared to Fulvestrant. Does not impact apoptosis in MCF7 breast cancer cells. ER+ MCF-7 cells are seeded in 96-well plates and treated with Rintodestrant (0.01 nM-10 uM) for 72 h. Cell viability is measured by CellTiter-Glo assay to calculate IC50 for growth inhibition. For degradation studies, cells are treated for 6-24 h, lysed, and ER protein levels are assessed by Western blot. Alternatively, ER target genes (e.g., GREB1, TFF1) are quantified by qPCR. |
| Animal Protocol |
Animal/Disease Models: MCF7 xenograft tumors[1] ].
Doses: 30 or 100 mg/kg. Route of Administration: PO daily for 28 days. Experimental Results: Demonstrated dose-dependent inhibition of TamR tumor growth. In vivo efficacy is evaluated in ER+ breast cancer xenograft mouse models (e.g., MCF-7 or patient-derived xenografts). Mice bearing tumors are treated orally with Rintodestrant (1-50 mg/kg) once daily for 2-4 weeks. Tumor volume is measured bi-weekly, and tumors are collected at study end for Western blot analysis of ER degradation. |
| ADME/Pharmacokinetics |
In preclinical animal models (mice, rats), Rintodestrant is well absorbed orally with moderate to high bioavailability. Plasma concentrations peak (Tmax) within 1-4 h post-dose, with terminal half-life (t1/2) ranging from 4-8 h depending on species. Exposure (AUC) increases proportionally with dose. The compound is primarily metabolized via CYP3A4.
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| Toxicity/Toxicokinetics |
In Phase 1 clinical trials (NCT03455270), Rintodestrant demonstrated an excellent safety and tolerability profile across all doses. No dose-limiting toxicities were identified. Most common adverse events were mild-to-moderate fatigue, nausea, and arthralgia. No significant safety concerns precluding further clinical development have been reported.
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| References | |
| Additional Infomation |
Rintodestrant is an orally administered selective estrogen receptor degrader/downregulator (SERD) with potential antitumor activity. After oral administration, ritextrin specifically targets and binds to estrogen receptor α (ERα; ESR1), inducing conformational changes that promote ERα degradation and downregulation. This blocks ERα-mediated signaling and inhibits the growth and survival of ERα-expressing cancer cells.
Rintodestrant has completed Phase 1 clinical trials for ER+, HER2- advanced or metastatic breast cancer (NCT03455270). Phase 1b expansion showed promising antitumor activity, including in patients with ESR1 mutations. It has not yet been approved for clinical use but remains under active investigation as both monotherapy and in combination with palbociclib. |
| Molecular Formula |
C26H19FO5S
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|---|---|
| Molecular Weight |
462.489469766617
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| Exact Mass |
462.093
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| CAS # |
2088518-51-6
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| Related CAS # |
2088518-51-6;
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| PubChem CID |
129205616
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| Appearance |
Solid powder
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| LogP |
6.6
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
724
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C2C=C(C=CC=2C(=C1C(C1C(C)=CC(=CC=1C)F)=O)OC1C=CC(/C=C/C(=O)O)=CC=1)O
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| InChi Key |
KOAITBOFZOEDOC-BJMVGYQFSA-N
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| InChi Code |
InChI=1S/C26H19FO5S/c1-14-11-17(27)12-15(2)23(14)24(31)26-25(20-9-6-18(28)13-21(20)33-26)32-19-7-3-16(4-8-19)5-10-22(29)30/h3-13,28H,1-2H3,(H,29,30)/b10-5+
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| Chemical Name |
(E)-3-[4-[[2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl]prop-2-enoic acid
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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 : 50 mg/mL (108.11 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.41 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 25.0 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: ≥ 2.5 mg/mL (5.41 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1622 mL | 10.8110 mL | 21.6221 mL | |
| 5 mM | 0.4324 mL | 2.1622 mL | 4.3244 mL | |
| 10 mM | 0.2162 mL | 1.0811 mL | 2.1622 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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