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| Targets |
SRI-41315 targets the eukaryotic release factor 1 (eRF1), a translation termination factor in eukaryotes primarily responsible for recognizing stop codons (UAA, UAG, and UGA) and catalyzing peptide release. As a molecular glue, it promotes the degradation of eRF1 through the proteasome-mediated pathway. By decreasing the abundance of eRF1, SRI-41315 inhibits premature termination codons (PTC) and promotes translational readthrough. It also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity.
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| ln Vitro |
Target cell cytotoxicity (CC50) values of >50 µM are demonstrated by SRI-41315 in both FRT and 16BE14o-cells [1]. Potency and efficacy of SRI-41315 are enhanced in FRT cells that are converted to 16HBE14o-cells [1]. eRF1 levels are reduced by SRI-41315 (5 µM, 20 hours) via the proteasome-mediated degradation pathway [1].
In vitro, SRI-41315 (5 µM, 20 hours) decreases eRF1 levels through the proteasome-mediated degradation pathway. It shows target cell cytotoxicity (CC50) values exceeding 50 µM in FRT cells and 16HBE14o- cells. The compound suppresses PTCs by reducing the abundance of the termination factor eRF1. It has also been shown to impact RPL12, RPL15 levels, and possibly eIF5A. |
| ln Vivo |
In vivo activity data for SRI-41315 are not detailed in the available literature. As a research compound, it could be tested in mouse models of cystic fibrosis to evaluate its ability to restore CFTR function and ameliorate disease symptoms. Its mechanism of action suggests it could promote readthrough of nonsense mutations in vivo.
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| Enzyme Assay |
In vitro non-cell-based assays for SRI-41315 involve measuring its binding to eRF1 and its ability to induce eRF1 degradation in cell-free systems. These assays may use purified components to study the molecular mechanism of action. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be used to measure binding affinity. Degradation assays can be performed using purified eRF1 and proteasome components.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: CFTR-G542X 16HBEge G542X Cell Tested Concentrations: 5 µM Incubation Duration: 20 hrs (hours) Experimental Results: Depletion of eRF1 levels via proteasome-mediated degradation pathway. Addition of (S)-MG132 prevented SRI-41315-mediated degradation of eRF1, but addition of the neddylation inhibitor MLN4924 did not. In vitro cell-based assays for SRI-41315 are conducted in cell lines with CFTR nonsense mutations, such as FRT and 16HBE14o- cells. Cells are treated with varying concentrations of SRI-41315 (e.g., 5 µM for 20 hours). eRF1 levels are measured by Western blotting. CFTR expression is assessed by Western blotting or immunofluorescence, and CFTR function is measured using functional assays such as Ussing chamber analysis or fluorescent dye efflux assays. Cytotoxicity is assessed using standard cell viability assays (e.g., CCK-8). |
| Animal Protocol |
In vivo animal experiments with SRI-41315 are not detailed in the available literature. As a research compound, it could be tested in mouse models of cystic fibrosis (e.g., CFTR knockout or nonsense mutation models). The compound could be administered orally or intraperitoneally. CFTR expression and function in tissues (e.g., lung, intestine) would be assessed, along with disease phenotypes such as survival and inflammation.
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| ADME/Pharmacokinetics |
SRI-41315 has a molecular weight of 357.41 g/mol and the formula C22H19N3O2. It is soluble in DMSO at 8.33 mg/mL (23.31 mM). As a powder, it is stable at -20°C for 3 years; in solvent, it is stable at -80°C for 1 year. Its purity is typically 99.87%.
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| Toxicity/Toxicokinetics |
Specific toxicological data for SRI-41315 are not detailed in the available literature. In cell-based assays, it shows low cytotoxicity with CC50 values >50 µM. As a research chemical, it is intended for laboratory use only and is not for human consumption. Standard laboratory safety precautions should be followed.
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| References | |
| Additional Infomation |
SRI-41315 is a first-in-class eRF1 degrader that acts as a molecular glue. It is a valuable tool for studying nonsense-mediated decay and has potential therapeutic applications for genetic diseases caused by nonsense mutations, such as cystic fibrosis. By decreasing eRF1 abundance, it inhibits premature termination codons and promotes translational readthrough.
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| Molecular Formula |
C22H19N3O2
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| Molecular Weight |
357.405164957047
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| Exact Mass |
357.147
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| CAS # |
1613509-49-1
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| PubChem CID |
76283898
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
27
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| Complexity |
715
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(C)C2=C(C=CC=C2)C(=O)C2C(=O)N(C3=CC=CC=C3)C(C3CCC3)=NC1=2
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| InChi Key |
XUOTZAUZHWCGHL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H19N3O2/c1-24-17-13-6-5-12-16(17)19(26)18-21(24)23-20(14-8-7-9-14)25(22(18)27)15-10-3-2-4-11-15/h2-6,10-14H,7-9H2,1H3
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| Chemical Name |
2-cyclobutyl-10-methyl-3-phenylpyrimido[4,5-b]quinoline-4,5-dione
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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 : ~20.83 mg/mL (~58.28 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 | 2.7979 mL | 13.9895 mL | 27.9791 mL | |
| 5 mM | 0.5596 mL | 2.7979 mL | 5.5958 mL | |
| 10 mM | 0.2798 mL | 1.3990 mL | 2.7979 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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