|-- -- --|
|Solubility (25°C) *||In vitro||DMSO||100 mg/mL (138.53 mM)|
|In vivo||2% DMSO+30% PEG 300+5% Tween 80+ddH2O||10mg/mL|
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
|Description||Tubacin is a highly potent and selective, reversible, cell-permeable HDAC6 inhibitor with an IC50 of 4 nM in a cell-free assay, approximately 350-fold selectivity over HDAC1.|
|In vitro||Tubacin, without directly stabilizing microtubules, induces an increase in α-tubulin acetylation with EC50 of 2.5 μM in A549 cells. Tubacin inhibits HDAC6-mediated α-tubulin deacetylation, and inhibits the migration of both wild-type and HDAC6-overexpressing cells.  Tubacin, in combination with paclitaxel, synergistically enhances tubulin acetylation.  Tubacin significantly inhibits both drug-sensitive and drug–resistant MM cell growth with IC50 of 5–20 μM, and induces cell apoptosis by activation of caspases. |
|In vivo||In chick embryos, inhibition of HDAC6 activity by Tubacin reduces the formation of new blood vessels in matrigel/nylon mesh. In angioreactors implanted in mice, Tubacin also impairs the formation of new blood vessels. |
|Features||The first known selective inhibitor of α-tubulin deacetylation.|
|Enzyme Inhibition Assay||Enzyme inhibition assays are performed using the Reaction Biology HDAC Spectrum platform. The HDAC1, 2, 4, 5, 6, 7, 8, 9, 10, and 11 assays used isolated recombinant human protein; HDAC3/NcoR2 complex is used for the HDAC3 assay. Substrate for HDAC1, 2, 3, 6, 10, and 11 assays is a fluorogenic peptide from p53 residues 379-382 (RHKKAc); substrate for HDAC8 is fluorogenic diacyl peptide based on residues 379-382 of p53 (RHKAcKAc). Acetyl-Lys(trifluoroacetyl)-AMC substrate is used for HDAC4, 5, 7, and 9 assays. Compounds are dissolved in DMSO and tested in 10-dose IC50 mode with 3-fold serial dilution starting at 30 μM. Control Compound Trichostatin A (TSA) is tested in a 10-dose IC50 with 3-fold serial dilution starting at 5 μM. IC50 values are extracted by curve-fitting the dose/response slopes.|
|Cell lines||Drug-sensitive (MM.1S, U266, INA-6, and RPMI8226) and drug-resistant (RPMI-LR5 and RPMI-Dox40) MM cell lines|
|Incubation Time||72 hours|
The inhibitory effect of bortezomib and/or tubacin on MM cell growth is assessed by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye absorbance. All experiments are performed in quadruplicate.
|Animal Models||Athymic nude mice implanted with angioreactors|
|Administration||Tubacin is filled in semiclosed angioreactors, and then implanted into the mice.|
Data from [Data independently produced by , , Nat Biotechnol, 2015, 33(4): 415-23 ]
Verification of Hdac6 deletion in knockout MEFs. Expression of HDAC6 and acetylation of tubulin were analyzed by immunoblotting.
Data from [Data independently produced by , , Oncogene, 2016, 35(18):2333-44]
Inhibition of HDAC6 by tubacin induced the acetylation and membrane translocation of wild-type PTEN, but not K163R mutant. U-87 MG or NCl-H1650 cells were transfected with EGFP-PTEN or EGFP-PTEN-K163R for 24 h and then treated with tubacin for 24 h. *P<0.01.
Acetylation site specificities of lysine deacetylase inhibitors in human cells. [Scholz C, et al. Nat Biotechnol, 2015, 10.1038/nbt.3130]PubMed: 25751058
Histone deacetylase 3 as a novel therapeutic target in multiple myeloma [Minami J, et al. Leukemia, 2014, 28(3):680-9]PubMed: 23913134
Epigenetic Reprogramming of the Type III Interferon Response Potentiates Antiviral Activity and Suppresses Tumor Growth. [Ding S ,et al. PLoS Biol, 2013, 12(1):e1001758]PubMed: 24409098
PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition [Meng Z, et al. Oncogene, 2015, 10.1038/onc.2015.293]PubMed: 26279303
Loss of α-Tubulin Acetylation Is Associated with TGF-β-induced Epithelial-Mesenchymal Transition. [Gu S, et al. J Biol Chem, 2016, 291(10):5396-405]PubMed: 26763233
PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition. [Meng Z, et al. Oncogene, 2016, 35(18):2333-44]PubMed: 26279303
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