title: Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells.
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.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.forename: Kyle V
authors.initials: KV
authors.lastname: Butler
authors.forename: Tatiana
authors.initials: T
authors.lastname: Akimova
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D002243:Carbolines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007166:Immunosuppressive Agents; D007211:Indoles; D053645:Interleukin-2 Receptor alpha Subunit; D011994:Recombinant Proteins; C553587:tubastatin A; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases