Tubastatin A HCl is a potent and selective HDAC6 inhibitor with IC50 values of 15 nM. Tubastatin A was substantially more selective than the known HDAC6 inhibitor Tubacin at all isozymes except HDAC8. In addition, Tubastatin A displayed over 1000-fold selectivity against all HDAC isoforms excluding HDAC8, where it displayed 54-fold selectivity. This compound displayed dose-dependent protection against HCA induced neuronal cell death starting at 5 μM with near complete protection at 10 μM.
|Cell lines||Primary cortical neuron|
|Preparation method||Neuroprotection Assays Primary cortical neuron cultures were obtained from the cerebral cortex of fetal Sprague-Dawley rats (embryonic day 17) as described previously. All experiments were initiated 24 h after plating. Under these conditions, the cells are not susceptible to glutamate-mediated excitotoxicity. For cytotoxicity studies, cells were rinsed with warm PBS and then placed in minimum essential medium (Invitrogen) containing 5.5 g/liter glucose, 10% fetal calf serum, 2 mM L-glutamine, and 100 µM cystine. Oxidative stress was induced by the addition of the glutamate analog homocysteate (HCA; 5 mM) to the media. HCA was diluted from 100-fold concentrated solutions that were adjusted to pH 7.5. In combination with HCA, neurons were treated with either TSA or Tubastatin A at the indicated concentrations. Viability was assessed after 24 h by MTT assay (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) method.|
|Concentrations||0, 1, 2.5, 5.0, 7.5 and 10 μM|
|Incubation time||24 h|
|Animal models||dextran sodium sulfate (DSS) and adoptive transfer models of colitis|
|Dosages||0.5 mg/kg of body weight/day|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
Actin filaments play a primary role for structural integrity and viscoelastic response in cells.
Ketene AN, et al. Integr Biol (Camb). 2012 May;4(5):540-9. PMID: 22446682.
Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.
Butler KV, et al. J Am Chem Soc. 2010 Aug 11;132(31):10842-6. PMID: 20614936.
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BRD73954 ia a potent and selective HDAC inhibitor with IC50 of 36 nM and 120 nM for HDAC6 and HDAC8, respectively.
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