Tubastatin A
Tubastatin A is a potent and selective inhibitor of HDAC6 with IC50 value of 15 nM [1].
Histone deacetylases (HDACs) and histone acetyltransferases (HATs) mediates the balance between histone deacetylation and acetylation. HDACs also regulate the acetylation status of signaling molecules, chaperones, and transcription factors that are non-histone proteins [2]. HDAC6 interacts with the HSP90 which is a molecular chaperone. The deacetylation of HSP90 by HDAC6 is important for the stability and of many client proteins including Bcr-Abl, c-Raf, and AKT. So, HDAC inhibitors have anti-cancer function [2].
Tubastatin A is a selective inhibitor of HDAC6 compared with other HDACs. Tubastatin A maintained an average 200-fold selectivity compared with class I HDACs. Tubastatin A displayed selectivity against all isoforms excluding HDAC8
over 1000-fold. Tubastatin A protected against HCA induced neuronal cell death in a dose-dependent manner. Tubastatin A induced the hyperacetylationof -tubulin at 2.5 μM[1]. In LPS stimulated human THP-1 macrophages, Tubastatin A displayed significant inhibition of IL-6and TNF with an IC50 of 712 nM and 212 nM [3]. Tubastatin A showed the inhibition of nitric oxide (NO) secretion with an IC50 of 4.2μM in murine Raw 264.7 macrophages [3]. Tubastatin-A also significantly inhibit cell proliferation at 10μM in KMCH cells [4].
Tubastatin A showed inhibition of paw volume at 30 mg/kg in an animal model of inflammation[3]. Tubastatin-A treatment reduced tumor growth and induces ciliogenesis in rat orthotopic model of cholangiocarcinoma at 10 mg/kg [4].
References:
1.Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP: Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc 2010, 132(31):10842-10846.
2.Kim HJ, Bae SC: Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res 2011, 3(2):166-179.
3.Vishwakarma S, Iyer LR, Muley M, Singh PK, Shastry A, Saxena A, Kulathingal J, Vijaykanth G, Raghul J, Rajesh N et al: Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int Immunopharmacol 2013, 16(1):72-78.
4.Gradilone SA, Radtke BN, Bogert PS, Huang BQ, Gajdos GB, LaRusso NF: HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Res 2013, 73(7):2259-2270.
- 1. Junqiao Fang, Shangzhi Shu, et al. "Histone deacetylase 6 controls cardiac fibrosis and remodelling through the modulation of TGF‐β1/Smad2/3 signalling in post‐infarction mice." J Cell Mol Med. 2024 Sep;28(17):e70063. PMID: 39232846
- 2. Batchingis Chinbold, Hyug Moo Kwon, et al. "TonEBP inhibits ciliogenesis by controlling aurora kinase A and regulating centriolar satellite integrity." Cell Commun Signal. 2024 Jul 3;22(1):348. PMID: 38961488
- 3. Cuiying Peng, Yilin Wang, et al. "Selective HDAC6 inhibition protects against blood–brain barrier dysfunction after intracerebral hemorrhage." CNS Neurosci Ther. 2023 Sep 4. PMID: 37665135
- 4. Xuan Li, Hexige Saiyin, et al."HDAC6 is critical for ketamine-induced impairment of dendritic and spine growth in GABAergic projection neurons." Acta Pharmacologica Sinica (2020). PMID:32939037
- 5. Huang Y, Yang W, et al."Droxinostat sensitizes human colon cancer cells to apoptotic cell death via induction of oxidative stress." Cell Mol Biol Lett. 2018 Jul 28;23:34. PMID:30065760
- 6. Topper MJ, Vaz M, et al. "Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer." Cell. 2017 Nov 30;171(6):1284-1300.e21. PMID:29195073
- 7. Carolina dos S. Passos, Nathalie Deschamps,et al. "Methods for addressing the protein-protein interaction between histone deacetylase 6 and ubiquitin." biorxiv.2017 October 15.
- 8. Adeegbe DO, Liu Y, et al. "Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer." Cancer Discov. 2017 Aug;7(8):852-867. PMID:28408401
- 9. Bagnall NH, Hines BM, et al."Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina." Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):51-60. PMID:28110187
- 10. Sun, Yuefeng, et al. "Fe65 Suppresses Breast Cancer Cell Migration and Invasion through Tip60 Mediated Cortactin Acetylation." Scientific reports 5 (2015). PMID:26166158
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 335.4 |
| Cas No. | 1252003-15-8 |
| Formula | C20H21N3O2 |
| Solubility | insoluble in EtOH; insoluble in H2O; ≥10.75 mg/mL in DMSO |
| Chemical Name | N-hydroxy-4-((2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)methyl)benzamide |
| SDF | Download SDF |
| Canonical SMILES | O=C(C1=CC=C(CN2C3=C(C4=C2C=CC=C4)CN(CC3)C)C=C1)NO |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Human breast cancer cells (MCF-7). |
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Preparation method |
Soluble in DMSO > 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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Reaction Conditions |
15, 30 μM; 48 h. |
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Applications |
In MCF-7 cells, tubastatin A inhibits cell proliferation in a dose-dependent way with IC50 value of 15 μM and increases the acetylation of cytoplasmic microtubules. Also, tubastatin A reduces the microtubule depolymerization rate induced by cold and 200 nM nocodazole, which is mediated by the inhibition of HDAC6. |
| Animal experiment [2]: | |
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Animal models |
Wistar rats; DBA1 mice |
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Dosage form |
Rats: 30 mg/kg/day i.p. for 5 days; mice: 30 mg/kg, q.d. from day 21 to day 36. |
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Preparation method |
Solubilized in 10% Dimethyl sulfoxide (DMSO) 10% Polyethylene glycol (PEG) 400 and 80% (40% of hydroxy propyl beta cyclodextrin). |
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Applications |
In FCA injected rats, tubastatin significantly reduces paw volume by 71.9% at 2 h. In DBA1 arthritis mouse induced by semi-therapeutic collagen, tubastatin (30 mg/kg/day, i.p.) significantly reduces arthritic clinical scores by 73% and inhibits the production of IL-6 in paw tissues by 59%. Tubastatin treated mice shows insignificant changes in body weight. |
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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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References: [1]. Asthana J, Kapoor S, Mohan R, et al. Inhibition of HDAC6 deacetylase activity increases its binding with microtubules and suppresses microtubule dynamic instability in MCF-7 cells. J Biol Chem, 2013, 288(31): 22516-22526. [2]. Vishwakarma S, Iyer LR, Muley M, et al. Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int Immunopharmacol, 2013, 16(1): 72-78. |
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| Description | Tubastatin A is a potent and selective inhibitor of HDAC6 with an IC50 value of 15 nM. | |||||
| Targets | HDAC6 | |||||
| IC50 | 15 nM | |||||
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