PUBLICATION
Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors
- Authors
- Sandrone, G., Cukier, C.D., Zrubek, K., Marchini, M., Vergani, B., Caprini, G., Fossati, G., Steinkühler, C., Stevenazzi, A.
- ID
- ZDB-PUB-211120-3
- Date
- 2021
- Source
- ACS Medicinal Chemistry Letters 12: 1810-1817 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 34795871 Full text @ ACS Med. Chem. Lett.
Citation
Sandrone, G., Cukier, C.D., Zrubek, K., Marchini, M., Vergani, B., Caprini, G., Fossati, G., Steinkühler, C., Stevenazzi, A. (2021) Role of Fluorination in the Histone Deacetylase 6 (HDAC6) Selectivity of Benzohydroxamate-Based Inhibitors. ACS Medicinal Chemistry Letters. 12:1810-1817.
Abstract
Nonselective histone deacetylase (HDAC) inhibitors show dose-limiting side effects due to the inhibition of multiple, essential HDAC subtypes that can be limited or prevented by restricting their selectivity. We herein report the crystal structures of zebrafish HDAC6 catalytic domain 2 (zHDAC6-CD2) in complex with the selective HDAC6 inhibitors ITF3756 and ITF3985 and shed light on the role of fluorination in the selectivity of benzohydroxamate-based structures over class I isoforms. The reason for the enhancement in the selectivity of the benzohydroxamate-based compounds is the presence of specific interactions between the fluorinated linker and the key residues Gly582, Ser531, and His614 of zHDAC6, which are hindered in class I HDAC isoforms by the presence of an Aspartate that replaces Ser531. These results can be used in the design and development of novel, highly selective HDAC6 inhibitors.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping