Switching the Switch: Ligand Induced Disulfide Formation in HDAC8.

Authors :: Jänsch N
Sugiarto WO
Muth M
Kopranovic A
Desczyk C
Ballweg M
Kirschhöfer F
Brenner-Weiss G
Meyer-Almes FJ
Source :: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2020 Oct 15; Vol. 26 (58), pp. 13249-13255. Date of Electronic Publication: 2020 Sep 11.
Publication Year :: 2020
Abstract: 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 Cys <subscript>102</subscript> and Cys <subscript>153</subscript> . 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.<br /> (© 2020 The Authors. Published by Wiley-VCH GmbH.)