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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620278
Title:
An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection.
Authors:
Wagner, F. F.; Lundh, M.; Kaya, T.; McCarren, P.; Zhang, Y-L; Chattopadhyay, S.; Gale, J. P.; Galbo, T.; Fisher, S. L.; Meier, B. C.; Vetere, A.; Richardson, S.; Morgan, Noel; Christensen, D. P.; Gilbert, T. J.; Hooker, J. M.; Leroy, M.; Walpita, D.; Mandrup-Poulsen, T.; Wagner, B. K.; Holson, E. B.
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.
Citation:
An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection. 2016, 11 (2):363-74 ACS Chem. Biol.
Publisher:
American Chemical Society
Journal:
ACS chemical biology
Issue Date:
19-Feb-2016
URI:
http://hdl.handle.net/11287/620278
DOI:
10.1021/acschembio.5b00640
PubMed ID:
26640968
Additional Links:
https://dx.doi.org/10.1021/acschembio.5b00640
Type:
Journal Article
Language:
en
ISSN:
1554-8937
Appears in Collections:
Honorary contracts publications; 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWagner, F. F.en
dc.contributor.authorLundh, M.en
dc.contributor.authorKaya, T.en
dc.contributor.authorMcCarren, P.en
dc.contributor.authorZhang, Y-Len
dc.contributor.authorChattopadhyay, S.en
dc.contributor.authorGale, J. P.en
dc.contributor.authorGalbo, T.en
dc.contributor.authorFisher, S. L.en
dc.contributor.authorMeier, B. C.en
dc.contributor.authorVetere, A.en
dc.contributor.authorRichardson, S.en
dc.contributor.authorMorgan, Noelen
dc.contributor.authorChristensen, D. P.en
dc.contributor.authorGilbert, T. J.en
dc.contributor.authorHooker, J. M.en
dc.contributor.authorLeroy, M.en
dc.contributor.authorWalpita, D.en
dc.contributor.authorMandrup-Poulsen, T.en
dc.contributor.authorWagner, B. K.en
dc.contributor.authorHolson, E. B.en
dc.date.accessioned2017-03-14T12:44:27Z-
dc.date.available2017-03-14T12:44:27Z-
dc.date.issued2016-02-19-
dc.identifier.citationAn Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection. 2016, 11 (2):363-74 ACS Chem. Biol.en
dc.identifier.issn1554-8937-
dc.identifier.pmid26640968-
dc.identifier.doi10.1021/acschembio.5b00640-
dc.identifier.urihttp://hdl.handle.net/11287/620278-
dc.description.abstractModulation 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.en
dc.language.isoenen
dc.publisherAmerican Chemical Societyen
dc.relation.urlhttps://dx.doi.org/10.1021/acschembio.5b00640en
dc.rightsArchived with thanks to ACS chemical biologyen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleAn Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection.en
dc.typeJournal Articleen
dc.identifier.journalACS chemical biologyen
dc.type.versionPublisheden

Related articles on PubMed

All Items in RD&E Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.