Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells

Jay H. Kalin, Kyle V. Butler, Tatiana Akimova, Wayne W. Hancock, Alan P. Kozikowski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)639-651
Number of pages13
JournalJournal of medicinal chemistry
Volume55
Issue number2
DOIs
StatePublished - Jan 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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