Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors

Andreas Sellmer; Hubert Stangl; Mandy Beyer; Elisabeth Grünstein; Michel Leonhardt; Herwig Pongratz; Emerich Eichhorn; Sigurd Elz; Birgit Striegl; Zsuzsa Jenei-Lanzl; Stefan Dove; Rainer H Straub; Oliver H Krämer; Siavosh Mahboobi

doi:10.1021/acs.jmedchem.7b01593

Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors

J Med Chem. 2018 Apr 26;61(8):3454-3477. doi: 10.1021/acs.jmedchem.7b01593. Epub 2018 Apr 6.

Authors

Affiliations

¹ Institute of Pharmacy, Faculty of Chemistry and Pharmacy , University of Regensburg , 93040 Regensburg , Germany.
² Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine , University Hospital , 93042 Regensburg , Germany.
³ Institute of Toxicology , University Medical Center Mainz , 55131 Mainz , Germany.
⁴ Technical University of Applied Sciences (OTH) Regensburg , 93053 Regensburg , Germany.
⁵ Regensburg Center of Biomedical Engineering (RCBE) , OTH and University Regensburg , 93053 Regensburg , Germany.
⁶ Dr. Rolf M. Schwiete Research Unit for Osteoarthritis , Orthopedic University Hospital, Friedrichsheim gGmbH , 60528 Frankfurt/Main , Germany.

PMID: 29589441
DOI: 10.1021/acs.jmedchem.7b01593

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.

Publication types

Research Support, Non-U.S. Gov't

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*
Benzamides / cerebrospinal fluid
Benzamides / pharmacology
Benzamides / therapeutic use*
Benzamides / toxicity
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

Substances

Anti-Inflammatory Agents
Antirheumatic Agents
Benzamides
Carbolines
Collagen Type II
Histone Deacetylase Inhibitors
Hydroxamic Acids
marbostat-100
Hdac6 protein, mouse
Histone Deacetylase 6