Tubastatin A

Catalog No.S8049

Tubastatin A is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in a cell-free assay. It is selective against all the other isozymes (1000-fold) except HDAC8 (57-fold).

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Tubastatin A Chemical Structure

Tubastatin A Chemical Structure
Molecular Weight: 335.4

Validation & Quality Control

Customer Product Validation(4)

Quality Control & MSDS

Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description Tubastatin A is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in a cell-free assay. It is selective against all the other isozymes (1000-fold) except HDAC8 (57-fold).
Targets HDAC6 [1]
(Cell-free assay)
IC50 15 nM
In vitro Tubastatin A is selective at all isozymes except HDAC8 and maintains over 1000-fold selectivity against all isoforms excluding HDAC8, where it has approximately 57-fold selectivity. Tubastatin A preferentially induces α-tubulin hyperacetylation at 2.5 μM. Slight induction of histone hyperacetylation is seen for Tubastatin A at 10 μM. Tubastatin A displays dose-dependent protection against homocysteic acid-induced neuronal cell death starting at 5 μM with near complete protection at 10 μM. [1] Tubastatin A (10 μM) induces an increase in acetylated-α-tubulin levels and the restoration of primary cilia expression in the cholangiocarcinoma cell lines (18-fold); and the restoration of primary cilia correlated with downregulated Hedgehog (Hh) and MAPK signaling pathways, as well as decreased cell proliferation rates (in average by 50%) and invasion (by 40%). [2] Tubastatin A shows significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM. Tubastatin A inhibits nitric oxide (NO) secretion in murine Raw 264.7 macrophages dose depenndently with an IC50 of 4.2 μM. [3]
In vivo Tubastatin A reduces the growth of cholangiocarcinoma in vivo. Tubastatin A (10 mg/kg) induces a 6-fold lower mean tumor weights in syngeneic rat orthotopic model of cholangiocarcinoma, and reduction of the ratios of tumor weight to liver weight and body weight (5- and 5.6-fold, respectively), as well as a greater frequency of ciliated cholangiocytes compared with controls (29% vs 1.4%). Tubastatin A significantly decreases the amount of PCNA-positive cells in the treated tumors compared with vehicle controls (34% vs 65%). [2] Tubastat A shows significant inhibition of paw volume at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. Tubastat A (30 mg/kg i.p.) significant attenuates clinical scores (~ 70%), and IL-6 expression in paw tissues of collagen induced arthritis DBA1 mouse. [3]
Features

Protocol(Only for Reference)

Kinase Assay: [4]

HDAC enzymatic assays Tubastatin A is dissolved and diluted in assay buffer (50 mM HEPES, pH 7.4, 100 mM KCl, 0.001% Tween-20, 0.05% BSA, and 20 μM tris(2-carboxyethyl)phosphine) to 6-fold of the final concentration. HDAC enzymes are diluted to 1.5-fold of the final concentration in assay buffer and pre-incubated with Tubastatin A for 10 minutes before the addition of the substrate. The amount of FTS (HDAC1, HDAC2, HDAC3, and HDAC6) or MAZ-1675 (HDAC4, HDAC5, HDAC7, HDAC8, and HDAC9) used for each enzyme is equal to the Michaelis constant (Km), as determined by a titration curve. FTS or MAZ-1675 is diluted in assay buffer to 6-fold the final concentration with 0.3 μM sequencing grade trypsin. The substrate/trypsin mix is added to the enzyme/compound mix and the plate is shaken for 60 seconds and then placed into a SpectraMax M5 microtiter plate reader. The enzymatic reaction is monitored for release of 7-amino-4-methoxy-coumarin over 30 minutes, after deacetylation of the lysine side chain in the peptide substrate, and the linear rate of the reaction is calculated.

Cell Assay: [2]

Cell lines Human cholangiocarcinoma cell lines HuCCT-1
Concentrations ~10 μM
Incubation Time 21 days
Method Anchorage-independent growth is assessed by growing cells in soft agar. About 25,000 cells suspended in 0.4% agar in culture media are layered over a 1% agar layer in a 6-well plate. Media are added twice a week and pictures are taken after 21 days of incubation. The number and size of colonies are analyzed using the Gel-Pro software.

Animal Study: [2]

Animal Models Rat cholangiocarcinoma xenografts BDEneu
Formulation
Dosages 10 mg/kg
Administration i.p. daily

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Butler KV, et al. J Am Chem Soc, 2010, 132(31), 10842-10846.

[2] Gradilone SA, et al. Cancer Res, 2013, 73(7), 2259-2270.

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Chemical Information

Download Tubastatin A SDF
Molecular Weight (MW) 335.4
Formula

C20H21N3O2

CAS No. 1252003-15-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 9 mg/mL (26.83 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 4% DMSO+30% PEG 300 5mg/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.
Chemical Name N-hydroxy-4-((2-methyl-2,3,4,5-tetrahydro-1H-indeno[1,2-c]pyridin-5-yl)methyl)benzamide

Customer Product Validation (4)


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Rating
Source Nat Commun 2014 5, 3479. Tubastatin A purchased from Selleck
Method Immunoblotting
Cell Lines RAW264.7
Concentrations 10 uM
Incubation Time 12 h
Results Most importantly, the augmented p38 phosphorylation caused by TBSA was abrogated by MEC17 knockdown (Lanes 19-24).

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Rating
Source Int J Cancer 2014 134(11):2560-71. Tubastatin A purchased from Selleck
Method Immunoprecipitations
Cell Lines H358 cells
Concentrations 5 uM
Incubation Time 96 h
Results When gefitinib, trichostatin A, or nicotinamide were administered alone, the interaction between BAX and Ku70 was strongly enhanced, whereas combination treatments (gefitinib with either trichostatin A or nicotinamide) decreased the interaction between BAX and Ku70, in agreement with the induction of apoptosis.

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Rating
Source J Biol Chem 2013 288(20), 14400-7. Tubastatin A purchased from Selleck
Method qRT-PCR
Cell Lines Triple-Negative Cancer Lines
Concentrations 1 uM
Incubation Time 24 h
Results Three of the five cell lines (MDA-MB-468, BT549, and HCC1937) showed suppression of mesenchymal gene expression following treatment with TSA, MS-275,or LBH589, and the other two (MDA-MB-231 and Hs578T) had amore modest reduction in mesenchymal gene expression. *p<0.05. Student’st test for mean of mesenchymal gene markers,for each drug-treated cell line compared withcontrol DMSO-treated cell line.

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Rating
Source J Biol Chem 2013 288(20), 14400-7. Tubastatin A purchased from Selleck
Method Western blot
Cell Lines NH1 cells
Concentrations 1,5 to 20 uM
Incubation Time 24 h
Results Only some and different HDACis reactivate HIV in HeLa cells.A, NH1 cells were incubated with increasing concentrations of different HDACis or DMSO for 24 h (upper panel: SAHA from 0.5, 2 to 10 μM;MS-275 from 2,5 to 25 μM; ST-80 from 2.5,10 to 40 μM;TBSA from 1,5 to 20 μM). HIV reactivation was determined by measuring the luciferase activity in cell lysates.Values are presented as -fold activation over the DMSO control (left bar). Errorbars represent S.E. of mean of experiments performed in triplicate. Westernblotting for acetylated tubulin (lower panels, bar 1) and histone H3 (lowerpanels, bar 3) confirmed the specificity of HDAC inhibition. Amounts of totaltubulin and histone H3 as loading controls are presented in lower panel, bars2 and 4. B, NH1 cells were incubated with fixed concentrations of MS-275 (12.5 μM,bars3,4,7,8,11–14) alone or incombination with increasing concentrations of ST-80 as indicated (μM) for 24h. SAHA(bar 5; 5μM) and DMSO(bar 1)were included as controls. HIV LTR reactivation was determined by measuringrelative luciferase activities in cell lysates. Values are presented as -fold activation over the DMSO control. Error bars represent S.E. of mean of experiments performed in triplicate.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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