2. Academic Validation
  3. An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

  • ACS Chem Biol. 2016 Feb 19;11(2):363-74. doi: 10.1021/acschembio.5b00640.
Florence F Wagner 1,  Morten Lundh 2 3,  Taner Kaya 1,  Patrick McCarren 2,  Yan-Ling Zhang 1,  Shrikanta Chattopadhyay 2,  Jennifer P Gale 1,  Thomas Galbo 4,  Stewart L Fisher 5,  Bennett C Meier 2,  Amedeo Vetere 2,  Sarah Richardson 6,  Noel G Morgan 6,  Dan Ploug Christensen 3,  Tamara J Gilbert 2,  Jacob M Hooker 1 7,  Mélanie Leroy 1,  Deepika Walpita 2,  Thomas Mandrup-Poulsen 3 8,  Bridget K Wagner 2,  Edward B Holson 1
Affiliations

Affiliations

  • 1 Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
  • 2 Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
  • 3 Department of Biomedical Sciences, University of Copenhagen , Copenhagen 1165, Denmark.
  • 4 Department of Internal Medicine, Yale University , New Haven, Connecticut 06520, United States.
  • 5 SL Fisher Consulting, LLC , PO Box 3052, Framingham, Massachusetts 01701, United States.
  • 6 University of Exeter Medical School , RD&E Hospital, Wonford EX2 5DW, U.K.
  • 7 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Department of Radiology, Harvard Medical School , Charlestown, Massachusetts 02129, United States.
  • 8 Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm 171 77, Sweden.
PMID: 26640968 DOI: 10.1021/acschembio.5b00640
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.

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