TY - JOUR

T1 - An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection

AU - Wagner, Florence F

AU - Lundh, Morten

AU - Kaya, Taner

AU - McCarren, Patrick

AU - Zhang, Yan-Ling

AU - Chattopadhyay, Shrikanta

AU - Gale, Jennifer P

AU - Galbo, Thomas

AU - Fisher, Stewart L

AU - Meier, Bennett C

AU - Vetere, Amedeo

AU - Richardson, Sarah

AU - Morgan, Noel G

AU - Christensen, Dan Ploug

AU - Gilbert, Tamara J

AU - Hooker, Jacob M

AU - Leroy, Mélanie

AU - Walpita, Deepika

AU - Mandrup-Poulsen, Thomas

AU - Wagner, Bridget K

AU - Holson, Edward B

PY - 2016/2/19

Y1 - 2016/2/19

N2 - 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.

AB - 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.

U2 - 10.1021/acschembio.5b00640

DO - 10.1021/acschembio.5b00640

M3 - Journal article

C2 - 26640968

VL - 11

SP - 363

EP - 374

JO - A C S Chemical Biology

JF - A C S Chemical Biology

SN - 1554-8929

IS - 2

ER -