A potent HDAC6 inhibitor
Tubastatin A HCl is a selective inhibitor of HDAC6 with IC50 value of 15 nM [1].
HDAC6 (histone deacetylase 6) is an enzyme and plays an important role in a variety of processes, including transcriptional regulation, cell cycle preogression and developmental events. Abnormal expression of HDAC6 is correlated with many kinds of diseases, including Alzheimer's disease and cancers [1].
Tubastatin A HCl is a potent HDAC6 inhibitor and has the most selective compared with other HDAC isoforms. When tested with primary cortical neuron cells, Tubastatin A HCl treatment protected HCA-induced neuronal cell death in a dose range from 5 μM to 10 μM [1]. In HaCaT cells, administration of Tubastatin A HCl prevented sodium arsenite from inducing association of Nrf2 mRNA with ribosomes and elevation of Nrf2 protein by selectively inhibitng HDAC6 activity and had no effect on other HDACs [2]. Using atomic force microscopy study, Ketene AN et al. revealed that Tubastatin A HCl increased cell elasticity by inhibiting HDAC6 [3].
参考文献:
[1].? Kyle V. Butler, Jay Kalin, Camille Brochier, et al. Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A [J]. J. Am. Chem. Soc., 2010, 132 (31), pp 10842–10846.
[2].? Kappeler KV, Zhang J, Dinh TN, et al. Histone deacetylase 6 associates with ribosomes and regulates de novo protein translation during arsenite stress [J]. Toxicol Sci. 2012 May;127(1):246-255.
[3].? Ketene AN, Roberts PC, Shea AA, et al. Actin filaments play a primary role for structural integrity and viscoelastic response in cells [J]. Integr Biol (Camb). 2012 May;4(5):540-549.
| Kinase experiment [1]: | |
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Enzyme inhibition assays |
Isolated recombinant human protein was used for the HDAC1, 2, 4, 5, 6, 7, 8, 9, 10 and 11 assays, and HDAC3/NcoR2 complex was used for the HDAC3 assay. Substrate for HDAC1, 2, 3, 6, 10 and 11 assays was a fluorogenic peptide from p53 residues 379 ~ 382 (RHKKAc); substrate for HDAC8 was fluorogenic diacyl peptide based on residues 379 ~ 382 of p53 (RHKAcKAc). Acetyl-Lys (trifluoroacetyl)-AMC substrate was used for HDAC4, 5, 7 and 9 assays. Tubastatin A was dissolved in DMSO and tested in 10-dose IC50 mode with 3-fold serial dilution starting at 30 μM. Control Compound Trichostatin A was tested in a 10-dose IC50 with 3-fold serial dilution starting at 5 μM. IC50 values were extracted by curve-fitting the dose/response slopes. |
| Cell experiment [2]: | |
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Cell lines |
HaCaT cells |
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Preparation method |
The solubility of this compound in DMSO is > 18.6 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
10 μM; 10 hrs |
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Applications |
In HaCaT cells, Tubastatin A HCl selectively inhibited HDAC6, preventing sodium arsenite-induced association of Nrf2 mRNA with ribosomes and elevation of Nrf2 protein. |
| Animal experiment [3]: | |
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Animal models |
B6/Rag1-/- mice adoptively transferred with 1 × 106 WT CD4+ CD45RBhi cells |
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Dosage form |
25 mg/kg; i.p.; q.d., for 14 days |
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Applications |
Adoptively transferred B6/Rag1-/- mice which were treated with Tubastatin A HCl recovered body weights and normal stool formation. In addition, the histologic examination showed reduced mononuclear cell infiltration, preservation of goblet cells, as well as intact mucosal surfaces. |
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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]. Kyle V. Butler, Jay Kalin, Camille Brochier, et al. Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A [J]. J. Am. Chem. Soc., 2010, 132 (31), pp 10842–10846. [2]. Kappeler KV, Zhang J, Dinh TN, et al. Histone deacetylase 6 associates with ribosomes and regulates de novo protein translation during arsenite stress [J]. Toxicol Sci. 2012 May;127(1):246-255. [3]. de Zoeten EF, Wang L, Butler K, Beier UH, Akimova T, Sai H, Bradner JE, Mazitschek R, Kozikowski AP, Matthias P, Hancock WW. Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol Cell Biol. 2011 May;31(10):2066-78. | |
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