title: An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection.
abstract: Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.|Department of Biomedical Sciences, University of Copenhagen , Copenhagen 1165, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Lundh
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Taner
authors.initials: T
authors.lastname: Kaya
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: McCarren
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Shrikanta
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Gale
authors.affiliation: Department of Internal Medicine, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Galbo
authors.affiliation: SL Fisher Consulting, LLC , PO Box 3052, Framingham, Massachusetts 01701, United States.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Fisher
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Bennett C
authors.initials: BC
authors.lastname: Meier
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Vetere
authors.affiliation: University of Exeter Medical School , RD&E Hospital, Wonford EX2 5DW, U.K.
authors.forename: Sarah
authors.initials: S
authors.lastname: Richardson
authors.affiliation: University of Exeter Medical School , RD&E Hospital, Wonford EX2 5DW, U.K.
authors.forename: Noel G
authors.initials: NG
authors.lastname: Morgan
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen , Copenhagen 1165, Denmark.
authors.forename: Dan Ploug
authors.initials: DP
authors.lastname: Christensen
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Gilbert
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.|Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Department of Radiology, Harvard Medical School , Charlestown, Massachusetts 02129, United States.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Leroy
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Deepika
authors.initials: D
authors.lastname: Walpita
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen , Copenhagen 1165, Denmark.|Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm 171 77, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects*; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D051381:Rats
chemical_list: D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D006655:Histone Deacetylases