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| Targets |
20S Proteasome activator 1 targets the 20S proteasome, a core component of the ubiquitin-proteasome system responsible for degrading damaged or misfolded proteins. By activating the proteasome, it enhances the degradation of proteins, including the pathogenic α-synuclein A53T mutant. This mechanism is relevant for neurodegenerative diseases where protein aggregation is a hallmark, such as Parkinson's disease.
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| ln Vitro |
20S proteasome activator 1 (compound 19) (2.5-15 μM; 45 min), destroys 73% of α-synuclein at 10 μM and over 80% at 15 μM [1]. A53T mutants are reduced by 25% and Hek-293T cells transfected with A53T mutant α-synuclein plasmids are dose-dependently reduced by 20S proteasome activator 1 at 5 μM (5-15 μM; 24 hr). α-synuclein was enhanced during staining; at 15 μM, A53T α-synuclein dropped by 67% [1].
In vitro, 20S Proteasome activator 1 is a potent activator of the 20S proteasome. At 10 µM, it destroys 73% of α-synuclein, and at 15 µM, it destroys over 80%. It dose-dependently reduces A53T mutants in Hek-293T cells transfected with A53T mutant α-synuclein plasmids at 5-15 µM over 24 hours. These data demonstrate its potent activity in promoting α-synuclein degradation. |
| ln Vivo |
In vivo, 20S Proteasome activator 1 has shown potential for reducing the probability of disease by preventing the accumulation of pathogenic α-synuclein A53T mutants. Specific in vivo efficacy data, such as effects in animal models of Parkinson's disease, are not detailed in the available sources.
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| Enzyme Assay |
A cell-free assay for 20S Proteasome activator 1 would involve measuring its activation of 20S proteasome activity. In this assay, purified 20S proteasome is incubated with a fluorogenic peptide substrate in the presence of varying concentrations of the compound. The rate of substrate cleavage is measured, and the EC200 is calculated. For this compound, the EC200 values are 0.3 μM for trypsin-like sites, 0.7 μM for chymotrypsin-like sites, and 1.8 μM for caspase-like sites.
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| Cell Assay |
Cellular assays for 20S Proteasome activator 1 typically involve assessing its effects on protein degradation in cells. Cells expressing a reporter protein or a pathogenic protein like α-synuclein A53T are treated with the compound, and the levels of the protein are measured by Western blotting or fluorescence. The compound's ability to enhance the degradation of these proteins confirms its proteasome-activating activity.
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| Animal Protocol |
In vivo animal experiments for 20S Proteasome activator 1 are not described in the available sources. As a compound that activates the proteasome and promotes the degradation of pathogenic proteins, it could be evaluated in animal models of neurodegenerative diseases, such as the A53T α-synuclein transgenic mouse model. However, no specific protocols or data are provided.
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| ADME/Pharmacokinetics |
20S Proteasome activator 1 has a molecular formula of C27H19ClF2N2OS and a molecular weight of 492.97 g/mol. Its CAS number is 2761578-18-9. Specific pharmacokinetic parameters, such as half-life and bioavailability, are not provided in the available sources. As a research compound, it is intended for preclinical studies. For storage, the powder should be kept at -20°C.
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| Toxicity/Toxicokinetics |
Toxicity data for 20S Proteasome activator 1 are not provided in the available sources. As a research compound, it is intended for research use only and is not for human consumption. Standard laboratory safety precautions should be observed when handling this compound.
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| References | |
| Additional Infomation |
20S Proteasome activator 1 (CAS: 2761578-18-9) is a potent 20S proteasome activator. It is also known as compound 19. The compound has EC200 values of 0.3 μM (trypsin-like), 0.7 μM (chymotrypsin-like), and 1.8 μM (caspase-like). It prevents the accumulation of pathogenic α-synuclein mutants. It is not an approved drug and is strictly for research purposes.
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| Molecular Formula |
C27H19CLF2N2OS
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|---|---|
| Molecular Weight |
492.967371225357
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| Exact Mass |
492.087
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| CAS # |
2761578-18-9
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| PubChem CID |
164886633
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| Appearance |
White to off-white solid powder
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| LogP |
7.5
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
664
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC=C2C(=C1)N(C3=C(S2)C=CC(=C3)Cl)CCC(=O)N(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F
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| InChi Key |
ZFFNQHQEQWDWBM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H19ClF2N2OS/c28-18-5-14-26-24(17-18)31(23-3-1-2-4-25(23)34-26)16-15-27(33)32(21-10-6-19(29)7-11-21)22-12-8-20(30)9-13-22/h1-14,17H,15-16H2
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| Chemical Name |
3-(2-chlorophenothiazin-10-yl)-N,N-bis(4-fluorophenyl)propanamide
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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 (~202.85 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.07 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0285 mL | 10.1426 mL | 20.2852 mL | |
| 5 mM | 0.4057 mL | 2.0285 mL | 4.0570 mL | |
| 10 mM | 0.2029 mL | 1.0143 mL | 2.0285 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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