Chemical Fingerprinting

描述（由申请人提供）：尽管经过多年的努力，亨廷顿舞蹈病（HD）或其他神经退行性疾病还没有有效的治疗方法。HD的毒性原因尚不清楚，也没有明确的药物靶点。因此，有风险和受影响的个体不可避免地向临床疾病发展，这不仅提供了寻找疾病治疗方法的潜在紧迫性，而且还提供了开发生物标志物来预测治疗结果的进展。在上一个资助期内，我们发现了一个毒性氧化循环，其中突变HD蛋白和扩增突变在引起毒性方面存在合作。毒性发生在四个步骤，我们已经开发出了有希望的抑制剂。最有希望的化合物XJB-5-131具有线粒体靶向抗氧化特性。虽然难溶性，但单独给药可减轻hHdH150Q HD小鼠模型中所有明显的疾病病理特征。在更新中，我们建议改善XJB-5-131的药物样特性，并在同时靶向毒性氧化循环的多个步骤的“多命中”治疗中使用优化的类似物：(1)抑制蛋白质聚集的三环吡啶酮，(2)8-氧- g糖基化酶抑制剂，一种防止单链断裂并阻止DNA中CAG三核苷酸扩增的酶，以及(3)针对MSH2-MSH3的HDAC抑制剂，一种稳定DNA环以产生扩增的蛋白质。在Aim 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共同施用，以确定药理学，最佳模拟给药途径，每种抑制剂组合的最大耐受剂量，并根据最佳药物样性质优先进行体内试验。在目标2中，我们将使用运动功能、认知、组织病理学和线粒体活性等简单的体内终点来测试多次治疗的疗效，以跟踪治疗进展。我们将确定哪种化合物组合最有效地抵消由于突变HD蛋白表达引起的毒性。总之，目前还没有针对HD的治疗方法，也没有加速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靶点治疗策略提供了一种有前途的治疗方法，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.