Chemical Fingerprinting

描述(申请人提供)：尽管多年来的紧张努力，仍然没有有效的治疗方法来治疗亨廷顿病(HD)或其他神经退行性疾病。HD的毒性原因知之甚少，也没有明确的药物靶点。因此，高危和受影响的人无情地向临床疾病发展，不仅提供了潜在的紧迫性，不仅寻找疾病的治疗方法，而且开发生物标记物来预测治疗结果的进展。在上一次资助期间，我们发现了一个毒性氧化循环，在这个循环中，突变的HD蛋白和扩展突变之间存在合作，从而导致毒性。毒性发生在四个步骤中，我们已经开发出了每一个步骤的有前途的抑制剂。最有希望的化合物XJB-5-131具有线粒体靶向抗氧化特性。尽管它很难溶解，但在hHdH150Q小鼠HD模型中，单独给药可以减轻所有明显的疾病病理特征。在更新中，我们建议改善XJB-5-131的类药物性能，并在“多击中”治疗中使用优化的类似物，其中多个步骤的毒性氧化循环同时靶向：(1)用于抑制蛋白质聚集的三环吡喃酮，(2)8-oxo-G糖基酶的抑制剂，一种防止DNA单链断裂和停止CAG三核苷酸扩张的酶，以及(3)针对MSH2-MSH3的HDAC抑制剂，MSH2-MSH3是一种稳定DNA环以产生扩张的蛋白质。在目标1中，我们建议将我们最成功的化合物XJB-5-131与至少一种其他抑制剂联合应用，以确定药理作用、类似物的最佳给药途径、每种抑制剂组合的最大耐受量，并根据最佳的类药物特性优先进行体内试验。在目标2中，我们将使用简单的体内运动功能、认知、组织病理学和线粒体活性的终点来测试多次击打治疗的有效性，以跟踪治疗进展。我们将确定哪种化合物的组合在抵消由于突变HD蛋白的表达而产生的毒性方面最有效。总而言之，目前还没有治疗HD的方法，也没有加快寻找治疗方法的方法。迫切需要新的工具和方法。我们新发现的化合物和多点治疗策略提供了一种有希望的治疗方法，值得进一步测试以填补这些医学空白。

DESCRIPTION (provided by applicant): Despite years of intense efforts, there has been no effective therapeutic approach for Huntington's disease (HD) or other neurodegenerative diseases. The cause of toxicity in HD is poorly understood, and there is no well-defined drug target. Thus, at-risk and affected individuals inexorably progress toward clinical disease, providing an underlying urgency not only to find therapies for the disease, but also to develop biomarkers to predict the progress of therapeutic outcome. During the last funding period, we have discovered a toxic oxidation cycle in which there is cooperation between the mutant HD protein and the expansion mutation in causing toxicity. Toxicity occurs at four steps, and we have developed promising inhibitors to each one. The most promising compound, XJB-5-131, has a mitochondrial targeted antioxidant properties. Although it is poorly soluble, administration alone alleviates all of the obvious pathological features of disease in an hHdH150Q mouse model for HD. In the renewal, we propose to improve the drug-like properties of XJB-5-131 and use an optimized analog in a "multi-hit" therapy in which multiple steps of the toxic oxidation cycles are targeted simultaneously: (1) a tricyclic pyrone for inhibiting the protein aggregates, (2) inhibitors for 8-oxo-G glycosylase, an enzyme that prevents single strand breaks and stops CAG trinucleotide expansion in DNA, and (3) HDAC inhibitors that target MSH2-MSH3, a protein that stabilizes the DNA loops to create expansions. In Aim 1, we propose to co-administer our most successful compound, XJB-5-131, with at least one of the other inhibitors to determine the pharmacology, the optimal route of analog administration, the maximum tolerated dose of each inhibitor combination, and to prioritize in vivo testing according to the best drug-like properties. In Aim 2, we will test the efficacy of multi-hit treatment using simple in vivo endpoints of motor function, cognition, histopathology, and mitochondrial activity to follow therapeutic progression. We will identify which combination of compounds is most effective in offsetting toxicity due to expression of the mutants HD protein. In sum, there are no therapies for HD or methods to speed up the search for therapeutics. New tools and approaches are desperately needed. Our novel discovered compounds and the multi-hit strategy for therapy provide a promising therapeutic approach that warrants further testing to fill these medical gaps.