Rapid Generation of Isoform-Selective Histone Deacetylase Inhibitors

快速生成异构体选择性组蛋白脱乙酰酶抑制剂

• 批准号: 8030563
• 负责人: Joshua A Kritzer
• 金额: $ 18.54万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030563
• 关键词: Address; Affect; Animal Model; Anticonvulsants; Biological Assay; Cell Culture Techniques; Cells; Communities; Cyclic Peptides; Data; Development; Disease; Drug Design; Drug Kinetics; Eukaryotic Cell; Generations; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; In Vitro; Injury; Libraries; Malignant Neoplasms; Mammalian Cell; Measures; Methodology; Methods; Molecular Mechanisms of Action; Motor Neurons; Mutagenesis; Nervous system structure; Neurons; Neurosciences; Pattern; Pharmaceutical Chemistry; Principal Investigator; Protein Isoforms; Proteins; Recovery; Research; Research Personnel; Saccharomyces cerevisiae; Specificity; Structure-Activity Relationship; T-Lymphocyte; Therapeutic; Tissues; Toxic effect; Validation; Valproic Acid; Vorinostat; Yeasts; base; drug discovery; enzyme activity; high throughput screening; inhibitor/antagonist; innovation; nervous system disorder; new technology; new therapeutic target; novel; novel therapeutics; polyglutamine; post stroke; pre-clinical; preclinical study; protein protein interaction; success; therapeutic target; tool

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.

描述（由申请人提供）：组蛋白脱乙酰酶（HDAC）抑制剂对几种癌症的治疗潜力已得到证实。最近，HDAC参与已被证明在多聚谷氨酰胺重复障碍，运动神经元障碍，从中风后缺血性损伤的恢复。广谱HDAC抑制剂的应用已经在这些和其他神经系统疾病的动物模型中显示出活性。这些数据导致推测，选择性抑制神经元中的HDAC可能是神经系统疾病的可行治疗策略。尽管有十多年的药物发现研究，我们解决HDAC是否是神经系统疾病的实际治疗靶点的能力仍然受到亚型选择性抑制剂短缺的阻碍。异构体选择性HDAC抑制剂的开发是寻求神经系统疾病新治疗策略的关键未解决的问题。 该R21提案的目的是应用新型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，因为此类化合物对于解决HDAC是否是神经系统病症的实际治疗靶标是必要的。所提出的方法利用了主要研究者开发的一种新技术，可以快速筛选酵母酿酒酵母中数百万种环肽，用于抑制酶活性或蛋白质-蛋白质相互作用。环肽是一类未充分研究的化合物，具有选择性HDAC抑制的潜力，所提出的方法代表了HDAC环肽抑制剂的第一个高通量筛选方法。 将构建几种选择菌株并用于分离特异性HDAC的抑制剂和涉及HDAC的蛋白质-蛋白质相互作用的抑制剂。将使用基于体外蛋白质和细胞的测定来分析每种抑制剂，以定量测量HDAC抑制效力、HDAC选择性特征和抑制涉及HDAC的蛋白质-蛋白质相互作用的能力。这种方法代表了传统药物发现的一种快速，廉价的替代方案，非常适合开发新型HDAC抑制剂。一旦开发出来，环肽HDAC抑制剂将成为神经科学界的宝贵工具，也是药物发现的起点。 公共卫生关系：临床前数据表明，组蛋白脱乙酰酶（HDAC）与多聚谷氨酰胺重复序列疾病、运动神经元疾病、中风后缺血性损伤恢复和其他神经系统疾病有关。该项目采用创新的药物发现策略来产生新的HDAC抑制剂，这些抑制剂对许多HDAC亚型之一具有选择性。异构体选择性HDAC抑制剂的产生是重要的，因为此类化合物对于解决HDAC是否是神经系统病症的实际治疗靶标是必要的。