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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 8 Pg. 3454-3477 (04 26 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29589441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Anti-Inflammatory Agents (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Antirheumatic Agents (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Arthritis, Experimental (chemically induced, drug therapy)
• Arthritis, Rheumatoid (chemically induced, drug therapy)
• Benzamides (cerebrospinal fluid, pharmacology, therapeutic use, toxicity)
• Binding Sites
• Carbolines (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Cell Line, Tumor
• Collagen Type II
• HEK293 Cells
• Histone Deacetylase 6 (chemistry, metabolism)
• Histone Deacetylase Inhibitors (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Humans
• Hydroxamic Acids (chemical synthesis, pharmacology, therapeutic use, toxicity)
• Male
• Mice, Inbred DBA
• Molecular Docking Simulation
• Zebrafish