Switching the Switch: Ligand Induced Disulfide Formation in HDAC8

Human histone deacetylase 8 is a well‐recognized target for T‐cell lymphoma and particularly childhood neuroblastoma. PD‐404,182 was shown to be a selective covalent inhibitor of HDAC8 that forms mixed disulfides with several cysteine residues and is also able to transform thiol groups to thiocyanates. Moreover, HDAC8 was shown to be regulated by a redox switch based on the reversible formation of a disulfide bond between cysteines Cys102 and Cys153. This study on the distinct effects of PD‐404,182 on HDAC8 reveals that this compound induces the dose‐dependent formation of intramolecular disulfide bridges. Therefore, the inhibition mechanism of HDAC8 by PD‐404,182 involves both, covalent modification of thiols as well as ligand mediated disulfide formation. Moreover, this study provides a deep molecular insight into the regulation mechanism of HDAC8 involving several cysteines with graduated capability to form reversible disulfide bridges. Regulated by a redox switch: PD‐404,182 has been evaluated as an isoenzyme selective covalent inhibitor of HDAC8. HDAC8 belongs to the enzyme family of zinc‐dependent histone deacetylases and is known to be regulated by a redox switch. The enzyme plays an important role in several cancer diseases and particularly childhood neuroblastoma. This study provides deep insight in how HDAC8 enzyme activity is regulated by disulfide bonds induced by PD‐404,182.