Tubastatin A is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in cell-free assays.
Description :
Tubastatin A is a potent and selective HDAC6 inhibitor with IC50 of 15 nM in cell-free assays; displays 57-fold selectivity over HDAC8 and >1,000-fold selective against other HDAC isoforms; induces an increase in acetylated-α-tubulin levels and the restoration of primary cilia expression in the cholangiocarcinoma cell lines at 10 uM, shows significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with IC50 of 272 nM and 712 nM; reduces the growth of cholangiocarcinoma in vivo.
Tubastatin A is substantially selective for all 11 HDAC isoforms and maintains over 1000-fold selectivity against all isoforms excluding HDAC8, where it has approximately 57-fold selectivity. In homocysteic acid (HCA) induced neurodegeneration assays, Tubastatin A displays dose-dependent protection against HCA-induced neuronal cell death starting at 5 μM with near complete protection at 10 μM[1]. At 100 ng/mL Tubastatin A increases Foxp3+ T-regulatory cells (Tregs) suppression of T cell proliferation in vitro[2]. Tubastatin A treatment in CC12 cells would lead to myotube formation impairment when alpha-tubulin is hyperacetylated early in the myogenic process; however, myotube elongation occurs when alpha-tubulin is hyeperacetylated in myotubes[3]. A recent study indicates that Tubastatin A treatment increases cell elasticity as revealed by atomic force microscopy (AFM) tests without exerting drastic changes to the actin microfilament or microtubule networks in mouse ovarian cancer cell lines, MOSE-E and MOSE-L[4].
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]