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

Florence F Wagner; Morten Lundh; Taner Kaya; Patrick McCarren; Yan-Ling Zhang; Shrikanta Chattopadhyay; Jennifer P Gale; Thomas Galbo; Stewart L Fisher; Bennett C Meier; Amedeo Vetere; Sarah Richardson; Noel G Morgan; Dan Ploug Christensen; Tamara J Gilbert; Jacob M Hooker; Mélanie Leroy; Deepika Walpita; Thomas Mandrup-Poulsen; Bridget K Wagner; Edward B Holson

doi:10.1021/acschembio.5b00640

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

Florence F Wagner, Morten Lundh, Taner Kaya, Patrick McCarren, Yan-Ling Zhang, Shrikanta Chattopadhyay, Jennifer P Gale, Thomas Galbo, Stewart L Fisher, Bennett C Meier, Amedeo Vetere, Sarah Richardson, Noel G Morgan, Dan Ploug Christensen, Tamara J Gilbert, Jacob M Hooker, Mélanie Leroy, Deepika Walpita, Thomas Mandrup-Poulsen, Bridget K WagnerEdward B Holson

43 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	ACS chemical biology
Vol/bind	11
Udgave nummer	2
Sider (fra-til)	363-374
Antal sider	12
ISSN	1554-8929
DOI	https://doi.org/10.1021/acschembio.5b00640
Status	Udgivet - 19 feb. 2016

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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, N. G., Christensen, D. P., Gilbert, T. J., Hooker, J. M., Leroy, M., Walpita, D., Mandrup-Poulsen, T., ... Holson, E. B. (2016). An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection. ACS chemical biology, 11(2), 363-374. https://doi.org/10.1021/acschembio.5b00640

Wagner, 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, DP, Gilbert, TJ, Hooker, JM, Leroy, M, Walpita, D, Mandrup-Poulsen, T, Wagner, BK & Holson, EB 2016, 'An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection', ACS chemical biology, bind 11, nr. 2, s. 363-374. https://doi.org/10.1021/acschembio.5b00640

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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.",

author = "Wagner, {Florence F} and Morten Lundh and Taner Kaya and Patrick McCarren and Yan-Ling Zhang and Shrikanta Chattopadhyay and Gale, {Jennifer P} and Thomas Galbo and Fisher, {Stewart L} and Meier, {Bennett C} and Amedeo Vetere and Sarah Richardson and Morgan, {Noel G} and Christensen, {Dan Ploug} and Gilbert, {Tamara J} and Hooker, {Jacob M} and M{\'e}lanie Leroy and Deepika Walpita and Thomas Mandrup-Poulsen and Wagner, {Bridget K} and Holson, {Edward B}",

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AU - Wagner, Florence F

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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

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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.

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

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