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| Targets |
The Sec61 translocon (Sec61 complex). This is a heterotrimeric membrane protein complex (Sec61alpha, beta, gamma) that forms a gated channel in the ER membrane. Sec61-IN-2 is a selective inhibitor that binds to the translocon, likely at the lateral gate or pore, and competitively blocks the passage of nascent polypeptide chains into the ER lumen. This prevents the proper targeting, folding, and maturation of all proteins synthesized on the rough ER.
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| ln Vitro |
In cell-free systems, Sec61-IN-2 inhibits the translocation of newly synthesized proteins into ER-derived microsomes. This prevents the glycosylation of nascent proteins, which can be detected as a shift in molecular weight by gel electrophoresis. In cells, Sec61-IN-2 treatment leads to the accumulation of the secretory protein precursors in the cytoplasm. Because it blocks secretion and membrane protein biogenesis, it is expected to be broadly cytotoxic to dividing cells.
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| ln Vivo |
Detailed in vivo activity of Sec61-IN-2 has not been published. As an inhibitor of a fundamental, essential cellular process, it is expected to be highly toxic to animals if administered systemically, as it would block the function of countless secretory and membrane proteins. However, its potent bioactivity makes it a powerful tool for dissecting the biology of the secretory pathway in controlled cellular models. Its development is primarily as a research chemical and not a therapeutic.
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| Enzyme Assay |
A standard biochemical assay for Sec61 translocon activity is a cell-free translation/translocation assay. In this assay, mRNA encoding a model secretory protein (e.g., preprolactin) is translated in a rabbit reticulocyte lysate system supplemented with canine pancreatic microsomes. The test compound is included in the reaction. Translocation into the microsomes is assessed by protease protection; the translocated protein is protected from protease digestion and can be detected by SDS-PAGE and autoradiography. Inhibition is observed as the loss of a protected, glycosylated product.
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| Cell Assay |
A cellular assay for Sec61 activity involves treating cells (e.g., HEK293T) with the compound and then analyzing the processing of a secreted reporter protein, such as secreted alkaline phosphatase (SEAP). Cells are transfected with an expression plasmid for SEAP. After treatment, the culture supernatant is collected, and SEAP activity is measured using a colorimetric or chemiluminescent substrate. A decrease in activity indicates inhibition of secretion. Alternatively, the maturation of a cell surface receptor (e.g., VSV-G) can be tracked by western blot.
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| Animal Protocol |
In vivo studies are not typically performed with Sec61-IN-2 due to its anticipated high toxicity. However, to demonstrate on-target activity, an in vivo model where the Sec61 channel is inhibited locally or conditionally could be used. Alternatively, an animal model of cancer could be employed to see if the compound can suppress tumor growth, given that rapidly dividing cancer cells have a high demand for protein secretion. Such experiments are not currently documented in the product literature.
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| ADME/Pharmacokinetics |
Sec61-IN-2 is a small molecule with a molecular weight of 401.48 g/mol. For in vitro studies, it is typically dissolved in DMSO to a high stock concentration (e.g., 100 mg/mL). For in vivo use, the formulation would need to be optimized. The compound has a predicted logP value indicating lipophilicity, and its solubility in aqueous buffers is likely limited, requiring formulation with solubilizers like cyclodextrins or lipid-based carriers for injection. No PK data is available.
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| Toxicity/Toxicokinetics |
Toxicity is expected for Sec61-IN-2 due to its fundamental mechanism of action. The Sec61 complex is essential for the viability and function of all eukaryotic cells. Systemic inhibition would be lethal or highly toxic. Researchers should handle it with extreme caution and avoid any exposure. The compound is strictly for in vitro use as a chemical biology tool. Any in vivo use would require highly localized administration to avoid systemic toxicity.
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| References |
[1]. MCMINN, Dustin, et al. THIAZOLE DERIVATIVES AS PROTEIN SECRETION INHIBITORS. Patent WO2020176863.
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| Additional Infomation |
Sec61-IN-2 is a research chemical derived from a patent (WO2020176863). It is used to study the role of protein secretion in various biological processes, such as viral replication (many viruses require host protein secretion for exit) and cancer cell growth. The Sec61 translocon has recently emerged as a potential anti-cancer and anti-viral drug target, and this compound is a tool for exploring that hypothesis. It is not approved for clinical use. The CAS number 2484865-72-5 is for the free base form.
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| Molecular Formula |
C22H19N5OS
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|---|---|
| Molecular Weight |
401.48
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| Exact Mass |
401.131
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| CAS # |
2484865-72-5
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| PubChem CID |
163321135
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| Appearance |
Off-white to yellow solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
567
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(N=CC=C1)/C=C/C2=CSC(=N2)NC(=O)C3=CC=CN3CC4=CC=NC=C4
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| InChi Key |
PWRJGWUGWDERBT-VOTSOKGWSA-N
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| InChi Code |
InChI=1S/C22H19N5OS/c1-16-4-2-10-24-19(16)7-6-18-15-29-22(25-18)26-21(28)20-5-3-13-27(20)14-17-8-11-23-12-9-17/h2-13,15H,14H2,1H3,(H,25,26,28)/b7-6+
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| Chemical Name |
N-[4-[(E)-2-(3-methylpyridin-2-yl)ethenyl]-1,3-thiazol-2-yl]-1-(pyridin-4-ylmethyl)pyrrole-2-carboxamide
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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: ~100 mg/mL (~249.1 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.23 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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 (6.23 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 DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4908 mL | 12.4539 mL | 24.9078 mL | |
| 5 mM | 0.4982 mL | 2.4908 mL | 4.9816 mL | |
| 10 mM | 0.2491 mL | 1.2454 mL | 2.4908 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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