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

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

来源：ACS Chemical Biology, 2016, 11(2): 363-374.

DOI：10.1021/acschembio.5b00640

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 beta-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 beta-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 beta-cells from inflammatory cytokines and nutrient overload in diabetes.

• 出版日期2016-2
• 单位MIT