NVS1.1
Based on 1 Customer Validation
NVS1.1 is an orally active, blood-brain barrier-penetrant eRF1 degrader. NVS1.1 induces ubiquitination of eRF1 at Lys279, mediates proteasomal degradation via the E3 ubiquitin ligases RNF14 and RNF25 as well as the translational stress sensor GCN1, traps eRF1 at the ribosomal A-site, inhibits translation termination and triggers ribosome collision. As a readthrough enhancer, NVS1.1 enables near-cognate tRNA incorporation at premature termination codons by reducing intracellular eRF1 levels. NVS1.1 activates ribosome-associated quality control pathways via ribosome collision, including ubiquitination of small subunit ribosomal proteins. NVS1.1 restores functional full-length CFTR and IDUA proteins and reduces glycosaminoglycan accumulation in relevant models. NVS1.1 can be used in the research of cystic fibrosis and Hurler syndrome (mucopolysaccharidosis type I, MPS I).
Nur für Forschungszwecke. Wir verkaufen nicht an Patienten.
- Formel: C17H16ClN3O2S
- Molecular Weight:361.85
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Speicherung:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biologische Aktivität
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Chemical Information
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Lösungsmittel & Löslichkeit
- Protokoll
- Reinheit & Dokumentation
- Verweise
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Help & FAQs
Biologische Aktivität
Beschreibung
IC50 & Target
[1]|
eRF1 |
RNF14 |
RNF25 |
In Vitro
NVS1.1 (1-10 μM; 48 h) dose-dependently restores functional IDUA enzymatic activity in HEKR4 cells expressing the IDUAQ70X or IDUAW402X nonsense mutations[1].
NVS1.1 (0.1-10 μM for 7 days, 0-0.6 μM for 7 weeks) dose-dependently restores IDUA activity, reduces GAG accumulation, normalizes GUSB activity, and is accompanied by eRF1 depletion in primary fibroblasts from homozygous IDUAW402X Hurler syndrome patients[1].
NVS1.1 (0.00-5.00 μM; 8-24 h) increases the level of IDUA-W402X mRNA in primary fibroblasts from Hurler syndrome patients[1].
NVS1.1 (2.5 μM; 6 h) induces proteasomal degradation of eRF1 in HEKR4 PTC reporter cells, and this degradation process does not require neddylation modification of Cullin-RING ligases[1].
NVS1.1 (25 μM; 30 min) induces ubiquitination modification of eRF1 in HeLa and HEKR4 PTC cells[1].
The process by which NVS1.1 (0.00-2.5 μM; 6 h) induces eRF1 degradation in HEKR4 PTC reporter cells requires the catalytically active E3 ubiquitin ligases RNF14 and RNF25[1].
The nonsense codon readthrough-inducing effect of NVS1.1 (0.1-10 μM; 24 h) in HEKR4 PTC reporter cells depends on catalytically active RNF14 and RNF25[1].
NVS1.1 (2.5 μM; 6 h) requires GCN1 to induce the degradation of eRF1 in HEKR4 cells[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:Parental, RNF14/RNF25 knockout, and rescue HEKR4 PTC reporter cells
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Concentration:0, 0.16, 0.31, 0.63, 1.25, 2.50 μM
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Incubation Time:6 h
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Result:Decreased eRF1 levels in a dose-dependent manner in parental cells.
Rendered cells resistant to NVS1.1-induced eRF1 degradation in RNF14 or RNF25 knockout cells.
Restored NVS1.1 sensitivity in rescue cell lines expressing wild-type RNF14 or RNF25, while catalytically inactive mutants (RNF14 C220S, RNF25 C135S/C138S) did not.
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Cell Line:primary Hurler syndrome fibroblasts
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Concentration:0, 0.76, 1.95, 5
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Incubation Time:8, 16, 24 h
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Result:Did not affect IDUA-W402X mRNA levels in primary Hurler syndrome fibroblasts at concentrations ≤2 μM across 8-24 h, but increased mRNA levels at 5 μM after 16-24 h
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Wistar Kyoto (homozygous for IDUA-W401X mutation; male and female; 8-10 weeks old; 200-300 g)[1]
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Dosage:20 mg/kg; 40 mg/kg
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Administration:p.o.; daily; 14 days
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Result:Restored approximately 1% of the IDUA activity measured in brain tissue of untreated wild-type rats (40 mg/kg dose).
Reduced brain GAG levels by 57% (40 mg/kg dose).
Reduced GUSB activity to approximately 1.3-fold of wild-type levels (40 mg/kg dose).
Reduced brain GAG levels by 36% (20 mg/kg dose).
Chemical Information
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Appearance Solid
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Molecular Weight 361.85
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Formel C17H16ClN3O2S
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SMILES
N[C@H](C1=CC=CC=C1)C(C=C2S(=O)(C)=O)=C(C=C2C3=CC=NN3)Cl
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Lösungsmittel & Löslichkeit
In Vitro:
DMSO : 100 mg/mL (276.36 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
Reinheit & Dokumentation
Verweise
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 2.7636 mL | 13.8179 mL | 27.6358 mL | 69.0894 mL |
| 5 mM | 0.5527 mL | 2.7636 mL | 5.5272 mL | 13.8179 mL | |
| 10 mM | 0.2764 mL | 1.3818 mL | 2.7636 mL | 6.9089 mL | |
| 15 mM | 0.1842 mL | 0.9212 mL | 1.8424 mL | 4.6060 mL | |
| 20 mM | 0.1382 mL | 0.6909 mL | 1.3818 mL | 3.4545 mL | |
| 25 mM | 0.1105 mL | 0.5527 mL | 1.1054 mL | 2.7636 mL | |
| 30 mM | 0.0921 mL | 0.4606 mL | 0.9212 mL | 2.3030 mL | |
| 40 mM | 0.0691 mL | 0.3454 mL | 0.6909 mL | 1.7272 mL | |
| 50 mM | 0.0553 mL | 0.2764 mL | 0.5527 mL | 1.3818 mL | |
| 60 mM | 0.0461 mL | 0.2303 mL | 0.4606 mL | 1.1515 mL | |
| 80 mM | 0.0345 mL | 0.1727 mL | 0.3454 mL | 0.8636 mL | |
| 100 mM | 0.0276 mL | 0.1382 mL | 0.2764 mL | 0.6909 mL |
NVS1.1 Related Classifications
HY-177569 Related Classifications
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