Switching the Switch: Ligand Induced Disulfide Formation in HDAC8
Niklas Jänsch1, Wisely Oki Sugiarto1, Marius Muth1,2
1Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Stephanstraße 7, 64295, Darmstadt, Germany.
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 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.
Insights
The inhibitor PD-404,182 targets human histone deacetylase 8 (HDAC8), a key protein in neuroblastoma. This study reveals PD-404,182 inhibits HDAC8 through covalent modification and by inducing disulfide bond formation.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Human histone deacetylase 8 (HDAC8) is a validated therapeutic target for T-cell lymphoma and neuroblastoma.
- HDAC8 activity is regulated by a redox switch involving disulfide bond formation between Cys102 and Cys153.
- PD-404,182 is a selective covalent inhibitor of HDAC8, known to modify cysteine residues.
Purpose of the Study:
- To elucidate the distinct molecular mechanisms by which PD-404,182 inhibits HDAC8.
- To investigate the role of disulfide bond formation in PD-404,182-mediated HDAC8 inhibition.
- To gain deeper insight into the cysteine-mediated redox regulation of HDAC8.
Main Methods:
- Investigated the effects of PD-404,182 on HDAC8 activity and structure.
- Utilized biochemical assays to assess covalent modification and disulfide bond formation.
- Analyzed dose-dependent responses to PD-404,182 treatment.
Main Results:
- PD-404,182 induces dose-dependent formation of intramolecular disulfide bridges in HDAC8.
- The inhibition mechanism involves both covalent modification of thiols and ligand-mediated disulfide formation.
- Demonstrated graduated capability of different cysteines to form reversible disulfide bridges.
Conclusions:
- PD-404,182 employs a dual mechanism to inhibit HDAC8, involving covalent modification and redox-based disulfide bond induction.
- This study provides significant molecular insights into the complex redox regulation of HDAC8.
- Understanding these mechanisms may aid in the development of novel HDAC8-targeted therapies.
