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

基本信息

批准号：
8215725
负责人：
Joshua A Kritzer
金额：
$ 16.32万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215725
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 public health relevance success therapeutic target tool

项目摘要

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）抑制剂的治疗潜力已被证明对多种癌症。最近，HDAC 已在多聚谷氨酰胺重复疾病、运动神经元疾病和中风后缺血性损伤的恢复中得到证实。广谱 HDAC 抑制剂的应用已在这些和其他神经系统疾病的动物模型中显示出活性。这些数据引发了人们的猜测：选择性抑制神经元中的 HDAC 可能是治疗神经系统疾病的可行策略。尽管进行了十多年的药物发现研究，但我们解决 HDAC 是否是神经系统疾病的实际治疗靶点的能力仍然受到异构体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一个关键的未解决问题。 R21 提案的目标是应用一种新的药物发现策略来生成异构体选择性 HDAC 抑制剂。异构体选择性 HDAC 抑制剂的产生具有重要意义，因为此类化合物对于确定 HDAC 是否是神经系统疾病的实际治疗靶点是必要的。所提出的方法利用了首席研究员开发的一项新技术，可以快速筛选酿酒酵母中数百万个环肽，以寻找酶活性或蛋白质-蛋白质相互作用的抑制剂。环肽是一类尚未充分研究的化合物，已被证明具有选择性 HDAC 抑制的潜力，所提出的方法代表了第一个 HDAC 环肽抑制剂的高通量筛选方法。将构建并使用几种选择菌株来分离特定 HDAC 的抑制剂和涉及 HDAC 的蛋白质-蛋白质相互作用的抑制剂。将使用体外蛋白质和基于细胞的测定法对每种抑制剂进行分析，以定量测量 HDAC 抑制效力、HDAC 选择性概况以及抑制涉及 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，特别适合新型 HDAC 抑制剂的开发。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以及药物发现的起点。公共健康相关性：临床前数据表明组蛋白脱乙酰酶 (HDAC) 与多聚谷氨酰胺重复紊乱、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。该项目应用创新药物发现策略来生成新的 HDAC 抑制剂，这些抑制剂对多种 HDAC 亚型之一具有选择性。异构体选择性 HDAC 抑制剂的产生具有重要意义，因为此类化合物对于确定 HDAC 是否是神经系统疾病的实际治疗靶点是必要的。