| In Vitro | In vitro activity: As compared to the other class I and II histone deacetylases (HDACs) (HDAC1, 12 μM; HDAC2, 9 μM; HDAC3, 23μM; HDAC4, >33 μM; HDAC5, >33 μM; HDAC7, 13 μM; HDAC8, 120 nM; HDAC9, >33 μM), BRD73954 maintains excellent selectivity toward HDAC6 and HDAC8 with IC50 of 36 nM and 120 nM, respectively. Treatment with BRD73954 results in a robust increase in α -tubulin acetylation.
Kinase Assay: RD73954 ia a potent and selective HDAC inhibitor with IC50 of 36 nM and 120 nM for HDAC6 and HDAC8, respectively.
Cell Assay: BRD73954 is the first small molecule histone deacetylase (HDAC) inhibitor, capable of potently and selectively inhibiting both HDAC6 and HDAC8, despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our data demonstrate that meta substituents of phenyl hydroxamic acids are readily accommodated upon binding to HDAC6 and, furthermore, are necessary for the potent inhibition of HDAC8. At 10 ?M, BRD73954 treatment results in a robust increase in acetylation of α-tubulin, a known HDAC6 substrate, but not histone H3, a substrate for HDAC1, 2, and 3, in HeLa cells. |
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