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

• 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
• 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

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选范例来推进新型组蛋白脱乙酰酶（HDAC）抑制剂的治疗开发，该范例由亨廷顿病（HD）的细胞培养物、果蝇和小鼠模型组成。临床候选药物测试将包括全面的临床前评估，然后向美国 FDA 提交研究性新药申请。我们发现了一种新型 HDAC 抑制剂化学支架（庚二酸二苯酰胺），它可以有效逆转 HD 的 R6/2 小鼠模型中的疾病表型，同时没有显示任何急性或慢性毒性作用。我们手头有该分子的衍生物库，在本提案中，我们寻求 (1) 进行结构-活性关系筛选，以鉴定 HDAC 抑制剂，这些抑制剂可逆转含有 PolyQ 的纹状体细胞中的基因表达变化并改变组蛋白乙酰化，作为 HD 的细胞模型；在果蝇模型中筛选我们的 HDAC 抑制剂库以进行 PolyQ 扩展，以确定逆转神经变性的体内效力，并确定 HDAC 酶特异性和体内活性之间的关系；表征啮齿动物体内 HD 活性化合物的体内药理学特性。 (2) 在R6/2 HD转基因小鼠中测试细胞和果蝇筛选中确定的顶级候选分子； (3) 创建 HD 靶向化合物库，以优化安全性、药理学和效力，以期开发长期口服剂量治疗。将在基于细胞和果蝇模型以及体内药理学中评估化合物的 HDAC 抑制活性和效力；在 R6/2 小鼠模型中测试上述确定的前 5 种化合物，并在 HD 的 YAC128 小鼠模型中测试两种最好的化合物，该模型表达全长突变亨廷顿蛋白，以减少替代功效中动物模型偏差的可能性。 (4) 将确定啮齿动物和非啮齿动物中前两种化合物的试验毒性和安全性，以帮助选择最终的临床候选药物；将开发临床级药品的生产方法；并且，将完成指导人体测试的药理学、安全性和毒理学一揽子新药临床试验（IND）。 公共健康相关性：我们最近发现了一类称为组蛋白脱乙酰酶 (HDAC) 抑制剂的小分子，可预防亨廷顿病 (HD) 小鼠模型的神经变性，并且没有其他研究中其他类型的 HDAC 抑制剂遇到的毒性问题。在此应用中，我们试图探索这些 HDAC 抑制剂作为 HD 的潜在治疗方法。