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ACS Chem Biol DOI:10.1021/acschembio.5b00640

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

Publication TypeJournal Article
Year of Publication2016
AuthorsWagner, FF, Lundh, M, Kaya, T, McCarren, P, Zhang, Y-L, Chattopadhyay, S, Gale, JP, Galbo, T, Fisher, SL, Meier, BC, Vetere, A, Richardson, S, Morgan, NG, Christensen, DPloug, Gilbert, TJ, Hooker, JM, Leroy, M, Walpita, D, Mandrup-Poulsen, T, Wagner, BK, Holson, EB
JournalACS Chem Biol
Volume11
Issue2
Pages363-74
Date Published2016 Feb 19
ISSN1554-8937
KeywordsAmino Acid Sequence, Animals, Apoptosis, Cell Line, Cytoprotection, Drug Design, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Insulin-Secreting Cells, Molecular Sequence Data, Protein Isoforms, Rats
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.

URLhttp://dx.doi.org/10.1021/acschembio.5b00640
DOI10.1021/acschembio.5b00640
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26640968?dopt=Abstract

Alternate JournalACS Chem. Biol.
PubMed ID26640968