Novel Histone Deacetylase Inhibitors as Therapeutics for Huntington's Disease

描述（由申请人提供）：本申请旨在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，该性能筛选范例由亨廷顿病（HD）的细胞培养、果蝇和小鼠模型组成。临床候选药物测试将包括完整的临床前评估，以向美国FDA提交研究性新药申请。我们已经确定了一种新的HDAC抑制剂化学支架（庚二苯酰胺），它在逆转HD的R6/2小鼠模型中的疾病表型方面是有效的，同时没有显示出急性或慢性毒性作用。我们手头上有该分子的衍生物库，并且在该提议中，我们寻求（1）进行结构-活性关系筛选以鉴定HDAC抑制剂，所述HDAC抑制剂在作为HD的细胞模型的含有polyQ的纹状体细胞中逆转基因表达变化并改变组蛋白乙酰化;在果蝇模型中筛选我们的HDAC抑制剂文库进行polyQ扩增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HD活性化合物在啮齿动物中的体内药理学性质。(2)在R6/2 HD转基因小鼠中测试在细胞和果蝇筛选中鉴定的最佳候选分子;（3）创建HD靶向化合物库，以优化安全性、药理学和效力，以预期开发长期口服剂量治疗。将评估化合物在基于细胞的模型和果蝇模型中的HDAC抑制活性和效力以及体内药理学;在R6/2小鼠模型中测试以上鉴定的前5种化合物，并在HD的YAC 128小鼠模型中测试两种最佳化合物，其表达全长突变亨廷顿蛋白以降低替代功效中动物模型偏倚的可能性。(4)将确定啮齿动物和非啮齿动物中前两种化合物的中试毒性和安全性特征，以帮助选择最终的临床候选药物;将开发临床级药物产品的生产方法;并将完成IND使能包药理学，安全性和毒理学，以指导人体试验。 公共卫生相关性：我们最近发现了一类称为组蛋白去乙酰化酶（HDAC）抑制剂的小分子，它可以预防亨廷顿病（HD）小鼠模型的神经变性，而没有其他研究中其他类型HDAC抑制剂遇到的毒性问题。在本申请中，我们寻求探索这些HDAC抑制剂作为HD的潜在治疗剂。

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.