PUBLICATION
Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 (HDAC6) Inhibitors
- Authors
- Vögerl, K., Ong, N., Senger, J., Herp, D., Schmidtkunz, K., Marek, M., Müller, M., Bartel, K., Shaik, T.B., Porter, N.J., Robaa, D., Christianson, D.W., Romier, C., Sippl, W., Jung, M., Bracher, F.
- ID
- ZDB-PUB-190116-9
- Date
- 2019
- Source
- Journal of medicinal chemistry 62(3): 1138-1166 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Acetylation
- Animals
- Catalytic Domain
- Cells, Cultured
- Crystallography, X-Ray
- HL-60 Cells
- Histone Deacetylase 6/antagonists & inhibitors*
- Histone Deacetylase 6/metabolism
- Histone Deacetylase Inhibitors/chemical synthesis*
- Histone Deacetylase Inhibitors/chemistry
- Histone Deacetylase Inhibitors/pharmacology*
- Humans
- Hydroxamic Acids/chemistry*
- In Vitro Techniques
- Microsomes, Liver/drug effects
- Microsomes, Liver/enzymology
- Microsomes, Liver/metabolism
- Molecular Docking Simulation
- Molecular Structure
- Phenothiazines/chemistry*
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 30645113 Full text @ J. Med. Chem.
Citation
Vögerl, K., Ong, N., Senger, J., Herp, D., Schmidtkunz, K., Marek, M., Müller, M., Bartel, K., Shaik, T.B., Porter, N.J., Robaa, D., Christianson, D.W., Romier, C., Sippl, W., Jung, M., Bracher, F. (2019) Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 (HDAC6) Inhibitors. Journal of medicinal chemistry. 62(3):1138-1166.
Abstract
The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here we report the preparation and systematic variation of phenothiazines and analogues containing a benzhydroxamic acid moiety as zinc-binding group. We evaluated their ability to inhibit selectively HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by Western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. . . The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping