Novel Histone Deacetylase Inhibitors as Therapeutics for Huntington's Disease

描述(由申请人提供)：这项申请寻求通过性能筛选范例推进一类新的组蛋白脱乙酰酶(HDAC)抑制剂的治疗开发，包括细胞培养、果蝇和亨廷顿病(HD)小鼠模型。临床候选测试将包括全面的临床前评估，导致向美国FDA提交研究性新药申请。我们已经确定了一种新型的HDAC抑制剂化学支架(苯并二苯酰胺)，它可以有效地逆转R6/2小鼠HD模型的疾病表型，而没有急性或慢性毒性作用。我们手头有这个分子衍生物的文库，在本建议中，我们试图：(1)进行结构活性关系筛选，以确定在含多聚Q的纹状体细胞中逆转基因表达变化和改变组蛋白乙酰化的HDAC抑制剂，作为HD的细胞模型；筛选我们的HDAC抑制物库，用于扩展多聚Q化合物，以确定在体内逆转神经变性的效力，并确定HDAC酶特异性和体内活性之间的关系；研究HD活性化合物在啮齿动物体内的药理学性质。(2)在R6/2 HD转基因小鼠中测试细胞和果蝇筛选中确定的首要候选分子；(3)创建HD靶向化合物库，以优化安全性、药理学和有效性，以期开发长期口服剂量治疗。将在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前5种化合物，并在YAC128小鼠HD模型中测试最好的两种化合物，该模型表达全长突变亨廷顿蛋白，以降低替代疗效中动物模型偏差的可能性。(4)将利用啮齿动物和非啮齿动物体内最大的两种化合物来确定试点毒性和安全性概况，以帮助选择最终的临床候选药物；将开发生产临床级药物产品的方法；并将完成指导人体测试的IND药理学、安全性和毒理学一揽子计划。 与公共健康相关：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，可以防止亨廷顿病(HD)小鼠模型的神经退化，而不会出现其他类型的HDAC抑制剂在其他研究中遇到的毒性问题。在本申请中，我们试图探索这些HDAC抑制剂作为治疗HD的潜在疗法。

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.