Novel Histone Deacetylase Inhibitors as Therapeutics for Huntington's Disease

新型组蛋白脱乙酰酶抑制剂治疗亨廷顿病

基本信息

批准号：
8080842
负责人：
JOEL M. GOTTESFELD
金额：
$ 158.87万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080842
关键词：
Acute Animal Model Canis familiaris Cardiovascular system Cell Culture Techniques Cell model Cells Chemicals Chronic Clinical Clinical Trials Clinical assessments Corpus striatum structure Dose Drosophila genus Enzymes Gene Expression Genetic Hand Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Human Huntington Disease Investigational New Drug Application Length Libraries Methods Modeling Nerve Degeneration Oral Performance Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Preparation Production Property Rodent Safety Screening procedure Specificity Structure-Activity Relationship Testing Therapeutic Toxic effect Toxicokinetics Toxicology Transgenic Mice base disease phenotype good laboratory practice human Huntingtin protein in vivo in vivo Model mouse model mutant neurobehavioral novel phase 2 study polyglutamine pre-clinical prevent public health relevance respiratory scaffold small molecule therapeutic development

项目摘要

DESCRIPTION (provided by applicant): This application seeks to advance the therapeutic development of a new class of histone deacetylase (HDAC) inhibitors through a performance-screening paradigm, consisting of cell culture, Drosophila and mouse models of Huntington's disease (HD). Clinical candidate testing will include full pre-clinical assessment leading to submission of an Investigational New Drug application to the US FDA. We have identified a novel HDAC inhibitor chemical scaffold (pimelic diphenylamides) that is efficacious in reversing disease phenotype in the R6/2 mouse model for HD, while showing no acute or chronic toxic effects. We have on hand a library of derivatives of this molecule, and in this proposal, we seek to (1) perform a structure-activity relationship screen to identify HDAC inhibitors that reverse gene expression changes and alter histone acetylation in polyQ containing striatal cells as a cellular model for HD; screen our HDAC inhibitor library in a Drosophila model for polyQ expansion to determine in vivo potency in reversing neurodegeneration, and to determine the relationship between HDAC enzyme specificity and in vivo activity; to characterize the in vivo pharmacology properties of HD-active compounds in rodents. (2) Test the top candidate molecules identified in cell and Drosophila screens in R6/2 HD transgenic mice; (3) Create a HD-targeted library of compounds to optimize safety, pharmacology and potency in anticipation of developing long-term oral dose treatments. Compounds will be assessed for HDAC inhibition activity and potency in the cell-based and Drosophila models and in vivo pharmacology; test the top 5 compounds identified above in the R6/2 mouse model, and test the two best compounds in the YAC128 mouse model of HD, which expresses full-length mutant huntingtin protein to reduce potential for animal model bias in surrogate efficacy. (4) Pilot toxicity and safety profiles will be determined with the top two compounds in rodents and non-rodents to help choose the final clinical candidate; methods for production of clinical grade drug product will be developed; and, an IND enabling package of pharmacology, safety and toxicology to guide human testing will be completed. PUBLIC HEALTH RELEVANCE: We recently identified a class of small molecules called histone deacetylase (HDAC) inhibitors that prevent neurodegeneration in a mouse model for Huntington's disease (HD), without toxicity problems that have been encountered with other types of HDAC inhibitors in other studies. In this application we seek to explore these HDAC inhibitors as potential therapeutics for HD.

描述（由申请人提供）：本申请旨在通过性能筛查范式来推动新的组蛋白脱乙酰基酶（HDAC）抑制剂的治疗性开发，包括细胞培养，由亨廷顿氏病（HD）组成的细胞培养，果蝇和小鼠模型。临床候选测试将包括完整的临床前评估，导致向美国FDA提交研究新药申请。我们已经确定了一种新型的HDAC抑制剂化学支架（双苯二甲酰基），该支架在HD的R6/2小鼠模型中逆转疾病表型有效，同时没有急性或慢性毒性作用。我们手头上有一个该分子的衍生物库，在该提案中，我们试图（1）执行结构关系筛选，以鉴定逆转基因表达的HDAC抑制剂会改变基因表达并改变含有纹状体细胞的组蛋白乙酰化作为HD的细胞模型；在果蝇模型中筛选我们的HDAC抑制剂库，以确定逆转神经变性的体内效力，并确定HDAC酶特异性与体内活性之间的关系；为了表征啮齿动物中HD活性化合物的体内药理学特性。（2）测试R6/2 HD转基因小鼠中细胞和果蝇筛选中鉴定出的顶部候选分子；（3）创建一个针对高清的化合物库，以优化预期长期口服剂量治疗的安全性，药理学和效力。将评估基于细胞和果蝇模型以及体内药理学中HDAC抑制活性和效力的化合物。测试上面在R6/2小鼠模型中鉴定出的前5种化合物，并测试HD的YAC128小鼠模型中的两种最佳化合物，该化合物表达了全长突变的亨廷汀蛋白，以降低替代功效中动物模型偏置的潜力。（4）将用啮齿动物和非塑料中的前两种化合物确定试验性毒性和安全性概况，以帮助选择最终的临床候选者；将开发生产临床级药物产品的方法；而且，将完成一套药理学，安全性和毒理学的促成套餐，以指导人类测试。公共卫生相关性：我们最近确定了一类称为组蛋白脱乙酰基酶（HDAC）抑制剂的小分子，这些抑制剂可预防亨廷顿氏病小鼠模型（HD）中神经退行性的抑制剂，而没有毒性问题，而其他类型的HDAC抑制剂则在其他研究中遇到了毒性问题。在此应用中，我们试图探索这些HDAC抑制剂作为HD的潜在疗法。