HDAC3型
HDAC1型
组蛋白脱乙酰基酶
组蛋白
癌症研究
生物
细胞生物学
小分子
乙酰化
药理学
化学
生物化学
基因
作者
Florence F. Wagner,Morten Lundh,Taner Kaya,Patrick McCarren,Yanling Zhang,Shrikanta Chattopadhyay,Jennifer Gale,Thomas Galbo,Stewart L. Fisher,Bennett C. Meier,Amedeo Vetere,Sarah J. 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
标识
DOI:10.1021/acschembio.5b00640
摘要
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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