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：
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
项目类别：
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

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）：已经证明了几种癌症组蛋白脱乙酰基酶（HDAC）抑制剂的治疗潜力。最近，在多谷氨酰胺重复疾病，运动神经元疾病和卒中后缺血性损伤中恢复中，HDAC受累已被证明。广谱HDAC抑制剂的应用显示在这些和其他神经系统疾病的动物模型中的活性。这些数据导致人们猜测，神经元中HDAC的选择性抑制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，但我们能够解决HDAC是否是神经系统疾病的实际治疗靶点的能力仍然受到同工型选择性抑制剂的短缺的阻碍。同工型选择性HDAC抑制剂的开发是追求新颖的神经系统疾病治疗策略的关键问题。该R21提案的目的是应用一种新型的药物发现策略来产生同工型选择性HDAC抑制剂。同工型选择性HDAC抑制剂的产生是重要的，因为这种化合物对于解决HDAC是否是神经系统疾病的实际治疗靶标的必要。所提出的方法利用了主要研究者开发的一种新技术，可以快速筛选酿酒酵母中的数百万个环状肽，用于用于酶活性或蛋白质 - 蛋白质相互作用的抑制剂。环状肽是一类未经展开的化合物，具有选择性HDAC抑制的潜力，并且所提出的方法代表了HDACS的环状肽抑制剂的第一种高通量筛选方法。将构建并使用几种选择菌株，以分离涉及HDAC的蛋白质蛋白相互作用的特定HDAC和抑制剂的抑制剂。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选择性谱以及抑制涉及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快速，廉价替代品，非常适合开发新型HDAC抑制剂。一旦开发，环状肽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。公共卫生相关性：临床前数据涉及组蛋白脱乙酰基酶（HDACS）在聚谷氨酰胺重复疾病，运动神经元疾病，中风后缺血性损伤和其他神经系统疾病中恢复。该项目采用创新的药物发现策略来产生新的HDAC抑制剂，这些抑制剂是对许多HDAC同工型之一的选择性。同工型选择性HDAC抑制剂的产生是重要的，因为这种化合物对于解决HDAC是否是神经系统疾病的实际治疗靶标的必要。