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

  • 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.

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Metadaten
Author:Andreas SellmerORCiD, Hubert Stangl, Mandy Beyer, Elisabeth Grünstein, Michel Leonhardt, Herwig Pongratz, Emerich Eichhorn, Sigurd Elz, Birgit Striegl, Zsuzsa Jenei-Lanzl, Stefan Dove, Rainer H. StraubORCiD, Oliver H. KrämerORCiD, Siavosh Mahboobi
DOI:https://doi.org/10.1021/acs.jmedchem.7b01593
Parent Title (English):Journal of medicinal chemistry
Publisher:ACS Publications
Document Type:Article
Language:English
Year of first Publication:2018
Release Date:2022/03/29
Tag:Animals; anti-Inflammatory agent; chemical synthesis; pharmacology; therapeutic use; toxicity
Volume:61
Issue:8
First Page:3454
Last Page:3477
Institutes:Fakultät Maschinenbau
Regensburg Center of Biomedical Engineering - RCBE
Begutachtungsstatus:peer-reviewed
research focus:Lebenswissenschaften und Ethik
Licence (German):Keine Lizenz - Es gilt das deutsche Urheberrecht: § 53 UrhG