Human histoned eacetylase 8i saw ell-recognized target forT-cell lymphomaa nd particularly childhoodn euroblastoma. PD-404,182 was shown to be as elective covalent inhibitor of HDAC8t hat formsm ixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover,H DAC8 was shown to be regulated by ar edox switch based on the reversible formation of a disulfideb ond between cysteines Cys 102 andC ys 153 .T his study on the distinct effects of PD-404,182 on HDAC8 reveals that this compound induces the dose-dependent formationo fi ntramolecular disulfide bridges. Therefore,t he inhibition mechanism of HDAC8b yP D-404,182 involves both, covalentmodification of thiols as well as ligand mediated disulfide formation. Moreover,t his study provides ad eep moleculari nsighti ntot he regulation mechanismo fH DAC8i nvolvings everal cysteines with graduated capability to form reversible disulfide bridges.