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 Citations (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.

Original language	English
Journal	ACS chemical biology
Volume	11
Issue number	2
Pages (from-to)	363-374
Number of pages	12
ISSN	1554-8929
DOIs	https://doi.org/10.1021/acschembio.5b00640
Publication status	Published - 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, vol. 11, no. 2, pp. 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.",

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AU - Chattopadhyay, Shrikanta

AU - Gale, Jennifer P

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AU - Fisher, Stewart L

AU - Meier, Bennett C

AU - Vetere, Amedeo

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AU - Morgan, Noel G

AU - Christensen, Dan Ploug

AU - Gilbert, Tamara J

AU - Hooker, Jacob M

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AU - Holson, Edward B

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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

Abstract

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