PUBLICATION
Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors
- Authors
- Sellmer, A., Stangl, H., Beyer, M., Grünstein, E., Leonhardt, M., Pongratz, H., Eichhorn, E., Elz, S., Striegl, B., Jenei-Lanzl, Z., Dove, S., Straub, R.H., Krämer, O.H., Mahboobi, S.
- ID
- ZDB-PUB-190424-10
- Date
- 2018
- Source
- Journal of medicinal chemistry 61: 3454-3477 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Anti-Inflammatory Agents/chemical synthesis
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use*
- Anti-Inflammatory Agents/toxicity
- Antirheumatic Agents/chemical synthesis
- Antirheumatic Agents/pharmacology
- Antirheumatic Agents/therapeutic use*
- Antirheumatic Agents/toxicity
- Arthritis, Experimental/chemically induced
- Arthritis, Experimental/drug therapy*
- Arthritis, Rheumatoid/chemically induced
- Arthritis, Rheumatoid/drug therapy*
- Binding Sites
- Carbolines/chemical synthesis
- Carbolines/pharmacology
- Carbolines/therapeutic use
- Carbolines/toxicity
- Cell Line, Tumor
- Collagen Type II
- HEK293 Cells
- Histone Deacetylase 6/chemistry
- Histone Deacetylase 6/metabolism*
- Histone Deacetylase Inhibitors/chemical synthesis
- Histone Deacetylase Inhibitors/pharmacology
- Histone Deacetylase Inhibitors/therapeutic use*
- Histone Deacetylase Inhibitors/toxicity
- Humans
- Hydroxamic Acids/chemical synthesis
- Hydroxamic Acids/pharmacology
- Hydroxamic Acids/therapeutic use
- Hydroxamic Acids/toxicity
- Male
- Mice, Inbred DBA
- Molecular Docking Simulation
- Zebrafish
- PubMed
- 29589441 Full text @ J. Med. Chem.
Citation
Sellmer, A., Stangl, H., Beyer, M., Grünstein, E., Leonhardt, M., Pongratz, H., Eichhorn, E., Elz, S., Striegl, B., Jenei-Lanzl, Z., Dove, S., Straub, R.H., Krämer, O.H., Mahboobi, S. (2018) Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors. Journal of medicinal chemistry. 61:3454-3477.
Abstract
Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping