Rapid Generation of Isoform-Selective Histone Deacetylase Inhibitors

描述（由申请人提供）：组蛋白去乙酰化酶（HDAC）抑制剂的治疗潜力已被证明用于几种癌症。最近，HDAC参与了多聚谷氨酰胺重复障碍、运动神经元障碍和脑卒中后缺血性损伤的恢复。广谱HDAC抑制剂的应用在这些和其他神经系统疾病的动物模型中显示出活性。这些数据使人们推测，选择性抑制神经元中的hdac可能是神经系统疾病的一种可行的治疗策略。尽管经过了十多年的药物发现研究，但由于缺乏同种异构体选择性抑制剂，我们确定hdac是否是神经系统疾病的实际治疗靶点的能力仍然受到阻碍。开发异构体选择性HDAC抑制剂是寻求神经系统疾病新治疗策略的关键问题。这项R21提案的目的是应用一种新的药物发现策略来产生异构体选择性HDAC抑制剂。异构体选择性HDAC抑制剂的产生是重要的，因为这些化合物对于确定HDAC是否是神经系统疾病的实际治疗靶点是必要的。该方法利用了首席研究员开发的一项新技术，可以快速筛选酵母菌中的数百万环肽，以寻找酶活性或蛋白质-蛋白质相互作用的抑制剂。环肽是一类未被充分开发的化合物，具有选择性抑制HDAC的潜力，所提出的方法代表了HDAC环肽抑制剂的第一种高通量筛选方法。几个选择菌株将被构建并用于分离特异性hdac抑制剂和hdac蛋白相互作用抑制剂。每种抑制剂将使用体外蛋白质和基于细胞的分析来定量测量HDAC抑制效力、HDAC选择性谱和抑制涉及HDAC的蛋白质-蛋白质相互作用的能力。这种方法代表了一种快速、廉价的替代传统药物发现的方法，非常适合开发新型HDAC抑制剂。一旦开发，环肽HDAC抑制剂将成为神经科学界的宝贵工具以及药物发现的起点。

DESCRIPTION (provided by applicant): The therapeutic potential of histone deacetylase (HDAC) inhibitors has been demonstrated for several cancers. More recently, HDAC involvement has been demonstrated in polyglutamine repeat disorders, motor neuron disorders, and recovery from post-stroke ischemic injury. Application of broad-spectrum HDAC inhibitors has shown activity in animal models of these and other nervous system disorders. These data have led to speculation that selective inhibition of HDACs in neurons could be a viable therapeutic strategy for nervous system disorders. Despite over a decade of drug discovery research, our ability to address whether HDACs are practical therapeutic targets for nervous system disorders is still hampered by a shortage of isoform-selective inhibitors. Development of isoform-selective HDAC inhibitors is a key unsolved problem in the pursuit of novel therapeutic strategies for nervous system disorders. The objective of this R21 proposal is to apply a novel drug discovery strategy to generate isoform-selective HDAC inhibitors. The generation of isoform-selective HDAC inhibitors is significant because such compounds are necessary to address whether HDACs are practical therapeutic targets for nervous system disorders. The proposed approach takes advantage of a novel technology developed by the Principal Investigator to rapidly screen millions of cyclic peptides in the yeast Saccharomyces cerevisiae for inhibitors of enzyme activity or protein-protein interactions. Cyclic peptides are an underexplored class of compounds with proven potential for selective HDAC inhibition, and the proposed approach represents the first high-throughput screening method for cyclic peptide inhibitors of HDACs. Several selection strains will be constructed and employed to isolate inhibitors of specific HDACs and inhibitors of protein-protein interactions involving HDACs. Each inhibitor will be analyzed using in vitro protein and cell-based assays to quantitatively measure HDAC inhibitory potency, HDAC selectivity profiles, and ability to inhibit protein-protein interactions involving HDACs. This approach represents a rapid, inexpensive alternative to traditional drug discovery that is uniquely well-suited for the development of novel HDAC inhibitors. Once developed, cyclic peptide HDAC inhibitors will be valuable tools for the neuroscience community as well as starting points for drug discovery. PUBLIC HEALTH RELEVANCE: Preclinical data has implicated histone deacetylases (HDACs) in polyglutamine repeat disorders, motor neuron disorders, recovery from post-stroke ischemic injury, and other nervous system disorders. This project applies an innovative drug discovery strategy to generate new HDAC inhibitors that are selective for one of the many HDAC isoforms. The generation of isoform-selective HDAC inhibitors is significant because such compounds are necessary to address whether HDACs are practical therapeutic targets for nervous system disorders.