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C16 (GW-506033X; C-16; PKR Inhibitor) is a brain penetrant protein kinase (PKR) inhibitor with anti-inflammatory effects. The double-stranded RNA-dependent protein kinase (PKR), an apoptotic inducer, regulates much pro-inflammatory cytokine production. It binds the ATP-binding site of PKR and blocks autophosphorylation (IC50 =186-210 nM). It can decrease Aβ42-induced inflammatory cytokine release and apoptosis in neuronal cultures, and prevents neuroinflammation and neuronal loss in an acute excitotoxic rat model.
| ln Vitro |
In primary neuronal cultures, PKR-IN-C16 (compound C16) releases the PKR-induced translation block [1]. In SH-SY5Y cells, PKR-IN-C16 (0.1 or 0.3 μM; 24 hours) prevents endoplasmic reticulum stress-induced neuronal cell death [1]. In addition to inhibiting PKR phosphorylation, PKR-IN-C16 (1-1000 nM; 4 hours) also stops amyloid beta-induced caspase-3 activation in SH-SY5Y cells [2].
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| ln Vivo |
PKR-IN-C16 (compound C16) (60 or 600 μg/kg; i.p.; 3 times) prevents both the inflammatory response in the model and PKR-induced neuronal loss in rats. It also prevents quinolinic acid (QA)-induced acute excitotoxicity.
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| Cell Assay |
Western Blot Analysis[2]
Cell Types: Human SH-SY5Y Cell Tested Concentrations: 1, 10, 20, 200, 1000 nM Incubation Duration: 4 hrs (hours) Experimental Results: Significant levels of phosphorylated PKR in cells exposed to 20 μM beta-amyloid reduce. |
| Animal Protocol |
Animal/Disease Models: normotensive male Wistar rats, excitotoxic neuroinflammation model, unilateral striatal injection of quinolinic acid (QA) to induce inflammation [1]
Doses: 60 or 600 μg/kg Mode of Route of Administration: intraperitoneal (ip) injection; 24 hrs (hrs (hours)) before, 2 hrs (hrs (hours)) after QA injection and 24 hrs (hrs (hours)) after QA injection Experimental Results: diminished expression of PKR active catalytic domain, preventing contralateral IL-1β levels from increasing at 600 μg/kg (97% inhibition ). Neuronal loss induced by 600 μg/kg QA injection was diminished by 47%, and the number of positively cleaved caspase-3 neurons was diminished by 37%. |
| References |
[1]. Tronel C, et al. The specific PKR inhibitor C16 prevents apoptosis and IL-1β production in an acute excitotoxic rat model with a neuroinflammatory component. Neurochem Int. 2014 Jan;64:73-83.
[2]. Page G, et al. Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease. Neuroscience. 2006;139(4):1343-54. |
| Molecular Formula |
C13H8N4OS
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|---|---|
| Molecular Weight |
268.294
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| Exact Mass |
268.0419
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| CAS # |
608512-97-6
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| SMILES |
N1C=C(/C=C2/C3C(=CC=C4N=CSC4=3)NC/2=O)N=C1
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| Chemical Name |
6,8-dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one
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| Synonyms |
GW 506033XC16 GW-506033X PKR InhibitorGW506033X
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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 : ~10 mg/mL (~37.27 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (3.73 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 + to the above solution and mix evenly; then add 450 μL of 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7273 mL | 18.6366 mL | 37.2731 mL | |
| 5 mM | 0.7455 mL | 3.7273 mL | 7.4546 mL | |
| 10 mM | 0.3727 mL | 1.8637 mL | 3.7273 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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