Abstract
Second-generation Tubastatin A analogues were synthesized and evaluated for their ability to inhibit selectively histone deacetylase 6 (HDAC6). Substitutions to the carboline cap group were well-tolerated with substitution at the 2-position of both β- and γ-carbolines being optimal for HDAC6 activity and selectivity. Some compounds in this series were determined to have subnanomolar activity at HDAC6 with more than 7000 fold selectivity for HDAC6 versus HDAC1. Selected compounds were then evaluated for their ability to augment the immunosuppressive effect of Foxp3+ regulatory T cells. All compounds tested were found to enhance the ability of regulatory T cells to inhibit the mitotic division of effector T cells both in vitro and in vivo, suggesting that further investigation into the use of these compounds for the treatment of autoimmune disorders is warranted.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4 Antigens / metabolism
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Carbolines / chemical synthesis
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Carbolines / chemistry
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Carbolines / pharmacology
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Cell Proliferation / drug effects
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Forkhead Transcription Factors / metabolism*
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Histone Deacetylase 6
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Histone Deacetylase Inhibitors / chemical synthesis*
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / chemistry
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Immunosuppression Therapy
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Immunosuppressive Agents / chemical synthesis*
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Interleukin-2 Receptor alpha Subunit / metabolism
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Mice
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Mice, Inbred C57BL
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Mitosis / drug effects
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Recombinant Proteins / chemistry
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Structure-Activity Relationship
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / drug effects*
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
Substances
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CD4 Antigens
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Carbolines
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FOXP3 protein, human
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Forkhead Transcription Factors
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Immunosuppressive Agents
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Indoles
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Interleukin-2 Receptor alpha Subunit
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Recombinant Proteins
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tubastatin A
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HDAC6 protein, human
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Hdac6 protein, mouse
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Histone Deacetylase 6
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Histone Deacetylases