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 Mélanie, Walpita Deepika, Mandrup-Poulsen Thomas, Wagner Bridget K, Holson Edward B
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
Center for the Science of Therapeutics, Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02142, United States.
ACS Chem Biol. 2016 Feb 19;11(2):363-74. doi: 10.1021/acschembio.5b00640. Epub 2015 Dec 7.
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.
组蛋白去乙酰化酶（HDAC）活性的调节已被认为是多种疾病的一种潜在治疗策略。然而，由于缺乏选择性小分子抑制剂，很难剖析单个HDAC的作用。在此，我们报告了一系列高效且具有亚型选择性的I类HDAC抑制剂的合成，这些抑制剂是通过对临床经验丰富的HDAC抑制剂CI-994进行最小结构改变而合理设计的。我们使用这套等化学源或化学匹配抑制剂工具来探究I类HDAC在β细胞病理生物学中的作用，并首次证明对单个HDAC亚型的选择性抑制保留了有益的生物学活性并减轻了基于机制的毒性。如预期的那样，高度选择性的HDAC3抑制剂BRD3308抑制了炎症细胞因子或现在的糖脂毒性应激诱导的胰腺β细胞凋亡，并增加了功能性胰岛素释放。此外，BRD3308对人巨核细胞分化没有影响，而HDAC1和2的抑制剂具有毒性。我们的研究结果表明，选择性抑制HDAC3代表了一种潜在的治疗途径，可作为一种疗法来保护胰腺β细胞免受糖尿病中炎症细胞因子和营养过载的影响。
