A PKCα/β1 inhibitor
Go 6976 is a selective inhibitor of PKC with IC50 value of 20 nM [1] [2].
Protein kinase C (PKC) is a family of protein kinase enzymes and plays an important role in controlling the function of other proteins by the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins [1-3].
Go 6976 is a potent PKC inhibitor and has a more potent activity with the reported PKC inhibitor H-7. When tested with nRT cells, Go 6976 showed a marked decrease the baseline T-current amplitude nearly 40% at the dose of 10 μM by inhibiting Ca2+-dependent PKC pathway [3]. 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 [2].
It is also reported that Go 6976 is a potent inhibitor to EGFR and FLT3with IC50 value ranges from 0.033 nM to 3.3 μM and 0.7 nM, respectively [4] [5].
参考文献:
[1].? Gschwendt, M., et al., Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett, 1996. 392(2): p. 77-80.
[2].? Qatsha, K.A., et al., Go 6976, a selective inhibitor of protein kinase C, is a potent antagonist of human immunodeficiency virus 1 induction from latent/low-level-producing reservoir cells in vitro. Proc Natl Acad Sci U S A, 1993. 90(10): p. 4674-8.
[3].? Joksovic, P.M., et al., Mechanisms of inhibition of T-type calcium current in the reticular thalamic neurons by 1-octanol: implication of the protein kinase C pathway. Mol Pharmacol, 2010. 77(1): p. 87-94.
[4].? Taube, E., et al., A novel treatment strategy for EGFR mutant NSCLC with T790M-mediated acquired resistance. Int J Cancer, 2012. 131(4): p. 970-9.
[5].?? Yoshida, A., et al., Go6976, a FLT3 kinase inhibitor, exerts potent cytotoxic activity against acute leukemia via inhibition of survivin and MCL-1. Biochem Pharmacol, 2014. 90(1): p. 16-24.
| Cell experiment[1]: | |
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Cell lines |
HEL cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
4 h, 1 μM |
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Applications |
Go 6976 is a selective inhibitor of the calcium-dependent isozymes of protein kinase C (PKC) and has a direct and potent inhibitory effect on JAK2 in vitro. Go 6976 also blocked signalling, proliferation and survival in cells expressing TEL-JAK2 fusion protein. In primary acute myeloid leukaemia cells, treatment with Go 6976 reduced STAT phosphorylation and constitutive STAT activity. |
| Animal experiment [2]: | |
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Animal models |
6-8 week-old Balb/c mice |
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Dosage form |
2.5 mg/kg, i.p. |
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Application |
Go 6976 significantly inhibited LPS-induced protein kinase D activation, relieved LPS/D-GalN-induced liver injury and improved the survival of LPS/D-GalN-administered mice. Go 6976 could also inhibit the activation of mitogen-activated protein kinases (MAPKs), reduce expression of tumor necrosis factor-a (TNF-ɑ), and decrease apoptosis and myeloperoxidase (MPO) activity in liver of mice. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Grandage V L, Everington T, Linch D C, et al. Go 6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells[J]. British journal of haematology, 2006, 135(3): 303-316. [2]. Duan G J, Zhu J, Xu C Y, et al. Protective effect of Go 6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice[J]. Inflammation research, 2011, 60(4): 357-366. |
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