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Purity: ≥98%
Go6976 (also known as PD-40697) is a novel, potent and selective inhibitor of PKC (Protein Kinase C)with potential antitumor activity. It inhibits PKC, PKCα, and PKCβ1 with IC50s of 7.9 nM, 2.3 nM, and 6.2 nM, respectively. In T cell lines ACH-2 and U1 infected with HIV-1, Go 6976 treatment effectively blocked viral transcription induced by Bryostain 1 or tumor necrosis factor α which lead to the inhibition of intracellular viral protein synthesis and viral shedding and also blocked IL-6 mediated posttranscriptional inducetion of viral protein.
Targets |
Protein Kinase C (PKC) (IC50 = 20 nM)
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ln Vitro |
Go6976 is a highly effective PKC inhibitor in vitro (IC50 = 20 nM). Its structural similarity to staurosporine makes it the most potent PKC inhibitor[1]. Interestingly, Go6976 is also found to abrogate S and G2 arrest. Dose-response studies show that 30 nM Go6976 is sufficient to abrogate S-phase arrest in 6 hours and complete abrogation of G2 arrest followed by lethal mitosis in 24 hours. Incubation of cells with 100 nM Go6976 is sufficient to completely abrogate S and G2 arrest at 6 and 24 hours, respectively, and is only slightly less potent than in bovine serum. At the concentrations used, incubation of cells with UCN-01 or Go6976 alone does not reduce viability in comparison to control.
With U1 and ACH-2 cell lines representative of an HIV-1 postintegration state, the effect of Gö 6976, a synthetic inhibitor of PKC was tested. Gö 6976 is a nonglycosidic indolocarbazole found to potently inhibit HIV-1 induction by Bryostatin 1, tumor necrosis factor alpha, and interleukin 6. Gö 6976 effectively blocks viral transcription induced by Bryostatin 1 or tumor necrosis factor alpha that leads to the inhibition of intracellular viral protein synthesis and viral shedding. Gö 6976 also blocks interleukin 6-mediated posttranscriptional induction of viral proteins. The IC50 of Gö 6976 shows a 12- to 60-fold more potent effect than for H-7, another PKC inhibitor with a similar mechanism. The inhibitory effect is reduced when Gö 6976 is not added before or within 1 hr of induction by the potent PKC activator Bryostatin 1. However, U1 cells can be grown for long periods in a nontoxic concentration of Gö 6976 (300 nM), which confers virtual inhibition of HIV-1 induction without the development of resistance. Results indicate that inhibition of HIV-1 proviral induction from latent/low-level-producing infectious states with potent PKC inhibitors like Gö 6976 may represent an additional and promising antiviral approach. [1] We identified that the protein kinase C (PKC) inhibitor Gö6976 had a post-entry anti-influenza viral effect, by using a polymerase activity-based reporter assay. This inhibitory effect was observed for influenza virus-infected cells as well as for cells transiently transfected with constructs for the RNA polymerase complex. Importantly, the in vitro analysis of viral protein phosphorylation identified PKCalpha as a kinase phosphorylating PB1 and NS1, but not PB2, PA or NP. Gö6976 was able to block PKC-specific phosphorylation in vitro. Thus, our data suggest that PKC contributes to the phosphorylation of influenza PB1 and NS1 proteins which appears to be functionally relevant for both viral RNA polymerase activity and efficient viral replication[3]. |
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ln Vivo |
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Cell Assay |
Cells counting kit-8 assay [1]
K562 cells in logarithmic growth phase were collected and seeded into 96-well cell culture plates at a density of 5×103 cells/well. K562 cells were treated with 5 μM Go6976/Gö6976, 10 µM Gö6976, 0 μM Gö6976 + 2 μM imatinib, 5 μM Gö6976 + 2 μM imatinib, and 10 μΜ Gö6976 + 2 μM imatinib, and the control group was only treated with PBS. Five parallel wells were set in each group and cultured for 72 h. Ten microliters of Cell Counting Kit-8 (CCK-8) solution was added to each well. After incubation for 3 h at 37 °C in a 5% CO2 incubator, the absorbance at 450 nm was recorded. MTT assay [1] CD34+ cells and PBMCs in logarithmic growth phase were collected and seeded in 96-well cell culture plates at a density of 5×103 cells/well. CD34+ cells and PBMCs were treated with 0.5, 1.0, 2.5, and 5.0 μM Go6976/Gö6976 for 24 h. Five parallel wells were set in each group and cultured for 72 h. Then, 50 μL of 2 mg/mL MTT solution were added to each well, and the cells were cultured for 4 h and centrifuged at 2000 r/min for 10 min. The supernatant was discarded in the dark. Finally, 100 μL of DMSO were added to each well, the mixture was shaken for 5 min, and the absorbance of each well was read at 450 nm. |
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Animal Protocol |
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References |
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Additional Infomation |
Goe 6976 is an organic heterohexacyclic compound and an indolocarbazole. It has a role as an EC 2.7.11.13 (protein kinase C) inhibitor.
An inhibitor of calcium-dependent isoforms of protein kinase C. Human immunodeficiency virus (HIV-1) infection is followed by a period of latency or a low-level-persistent (LLP) state that results in an asymptomatic infection of the host. Productive viral expression may be triggered by a variety of activators including mitogens, antigens, and cytokines. Protein kinase C (PKC) has been shown to be important in the intracellular cascade of signals induced by such activators. With U1 and ACH-2 cell lines representative of an HIV-1 postintegration state, the effect of Gö 6976, a synthetic inhibitor of PKC was tested. Gö 6976 is a nonglycosidic indolocarbazole found to potently inhibit HIV-1 induction by Bryostatin 1, tumor necrosis factor alpha, and interleukin 6. Gö 6976 effectively blocks viral transcription induced by Bryostatin 1 or tumor necrosis factor alpha that leads to the inhibition of intracellular viral protein synthesis and viral shedding. Gö 6976 also blocks interleukin 6-mediated posttranscriptional induction of viral proteins. The IC50 of Gö 6976 shows a 12- to 60-fold more potent effect than for H-7, another PKC inhibitor with a similar mechanism. The inhibitory effect is reduced when Gö 6976 is not added before or within 1 hr of induction by the potent PKC activator Bryostatin 1. However, U1 cells can be grown for long periods in a nontoxic concentration of Gö 6976 (300 nM), which confers virtual inhibition of HIV-1 induction without the development of resistance. Results indicate that inhibition of HIV-1 proviral induction from latent/low-level-producing infectious states with potent PKC inhibitors like Gö 6976 may represent an additional and promising antiviral approach.[1] Objectives: Chronic myeloid leukemia (CML) is a malignant tumor of the blood system. Gö6976, as a type of indolocarbazole and shows strong antitumor effects, but there have been no reports on the effect of Gö6976 on CML. The objectives of this research were: (1) to explore the impact of Gö6976 on CML in vitro and in vivo; and (2) to explore the drug toxicity of Gö6976 to normal cells and animals.Methods:K562 cells and CML mice were used to explore the effect of Gö6976 on CML. Peripheral blood mononuclear cells (PBMCs), CD34+ cells, and healthy mice were used to explore the drug toxicity of Gö6976.Results: Cell experiments showed that Gö6976 could inhibit the proliferation of K562 cells and enhance the inhibitory effects of imatinib at 5 μM and 10 μM, but it had little effect on CD34+ cells or PBMCs at concentrations less than 5 μM. Animal experiments showed that 2.5 mg/kg Gö6976 could effectively inhibit the development of CML in mice, and it had almost no effects on healthy mice at 2.5 mg/kg and 10 mg/kg.Discussion: Because of the direct inhibitory effect of Gö6976 on CML and its pharmacological enhancement effect on imatinib, it is foreseeable that Gö6976 could become a new type of anti-CML medicine. And the further research is needed.Conclusion: Our findings verified that Gö6976 could effectively inhibit CML in vitro and in vivo, and it is almost nontoxic to hematopoietic cells, immune cells, and healthy mice.[4] |
Molecular Formula |
C24H18N4O
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Molecular Weight |
377.42
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Exact Mass |
378.148
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Elemental Analysis |
C, 76.17; H, 4.79; N, 14.81; O, 4.23
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CAS # |
136194-77-9
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Related CAS # |
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PubChem CID |
3501
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Appearance |
white solid powder
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Density |
1.4±0.1 g/cm3
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Boiling Point |
652.3±55.0 °C at 760 mmHg
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Flash Point |
348.3±31.5 °C
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Vapour Pressure |
0.0±2.0 mmHg at 25°C
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Index of Refraction |
1.774
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LogP |
3.48
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Hydrogen Bond Donor Count |
1
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Hydrogen Bond Acceptor Count |
2
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Rotatable Bond Count |
2
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Heavy Atom Count |
29
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Complexity |
730
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Defined Atom Stereocenter Count |
0
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SMILES |
N#CCCN(C1=C2C(CNC3=O)=C3C4=C1N(C)C5=C4C=CC=C5)C6=C2C=CC=C6
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InChi Key |
VWVYILCFSYNJHF-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C24H18N4O/c1-27-17-9-4-2-7-14(17)20-21-16(13-26-24(21)29)19-15-8-3-5-10-18(15)28(12-6-11-25)23(19)22(20)27/h2-5,7-10H,6,12-13H2,1H3,(H,26,29)
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Chemical Name |
3-(23-methyl-14-oxo-3,13,23-triazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4,6,8,10,15,17,19,21-nonaen-3-yl)propanenitrile
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Synonyms |
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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 |
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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) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (8.59 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 32.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 1.39 mg/mL (3.67 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 13.9 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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. View More
Solubility in Formulation 3: 1.39 mg/mL (3.67 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 0.5% CMC Na+1% Tween 80: 30mg/mL |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.6496 mL | 13.2478 mL | 26.4957 mL | |
5 mM | 0.5299 mL | 2.6496 mL | 5.2991 mL | |
10 mM | 0.2650 mL | 1.3248 mL | 2.6496 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.