Sellmer, Andreas and Stangl, Hubert and Beyer, Mandy and Gruenstein, Elisabeth and Leonhardt, Michel and Pongratz, Herwig and Eichhorn, Emerich and Elz, Sigurd and Striegl, Birgit and Jenei-Lanzl, Zsuzsa and Dove, Stefan and Straub, Rainer H. and Kraemer, Oliver H. and Mahboobi, Siavosh (2018) Marbostat-100 Defines a New Class of Potent and Selective Antiinflammatory and Antirheumatic Histone Deacetylase 6 Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 61 (8). pp. 3454-3477. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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-beta-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SUPPRESSES SYNOVIAL INFLAMMATION; INDUCED ARTHRITIS; RHEUMATOID-ARTHRITIS; BONE DESTRUCTION; HDAC6 INHIBITOR; BETA-CATENIN; ACETYLATION; EXPRESSION; TUBULIN; CELLS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Mar 2020 06:57 |
| Last Modified: | 20 Mar 2020 06:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14706 |
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