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式，包括细胞培养、果蝇和亨廷顿病（HD）小鼠模型，推进一类新的组蛋白去乙酰化酶（HDAC）抑制剂的治疗开发。临床候选测试将包括完整的临床前评估，从而向美国FDA提交新药研究申请。我们已经确定了一种新的HDAC抑制剂化学支架（苯乙烯二苯酰胺），可有效逆转R6/2 HD小鼠模型的疾病表型，同时无急性或慢性毒性作用。我们手头有该分子衍生物的文库，在本提案中，我们寻求(1)执行结构-活性关系筛选，以确定HDAC抑制剂，这些抑制剂可以逆转基因表达变化并改变含有多q的纹状体细胞中的组蛋白乙酰化，作为HD的细胞模型；在果蝇模型中筛选我们的HDAC抑制剂文库进行polyQ扩增，以确定体内逆转神经变性的效力，并确定HDAC酶特异性与体内活性之间的关系；表征hd活性化合物在啮齿动物体内的药理学特性。(2)在R6/2 HD转基因小鼠中对细胞筛选和果蝇筛选中筛选出的候选分子进行检测；(3)建立hd靶向化合物文库，优化安全性、药理学和效价，以期开发长期口服剂量治疗。化合物将在细胞和果蝇模型以及体内药理学中评估HDAC抑制活性和效力；在R6/2小鼠模型中测试上述鉴定出的前5个化合物，并在表达全长突变型亨廷顿蛋白的HD小鼠模型YAC128中测试两个最佳化合物，以减少替代疗效中动物模型偏差的可能性。(4)确定前两种化合物在啮齿动物和非啮齿动物中的初步毒性和安全性，以帮助选择最终的临床候选药物；开发临床级药品的生产方法；并且，将完成一套能够指导人体试验的药理学、安全性和毒理学方案。

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.