Development of novel small molecules for delaying the progression of muscular dy

描述（由申请人提供）：本提案的目的是开发新的小分子药物，用于治疗杜氏肌营养不良症和其他可能的肌营养不良症。我们选择了四个目标，如果蛋白质水平增加或减少，它们可以改变疾病过程。我们的四个靶标是：utrophin（UTRN）、肌生长抑制素（GDF 8）、胰岛素样生长因子（IGF-Ia）的Ia类剪接形式和α 7-整联蛋白（ITGA 7）。其他人（以及在某些情况下我们自己）的工作已经证明，肌营养蛋白、IGF-Ia或ITGA 7水平的适度增加可以显著改善小鼠中与肌营养不良蛋白和/或UTRN基因突变相关的肌无力。类似地，GDF 8的抑制已显示出改善在肌营养不良蛋白基因（mdx）小鼠中携带突变的小鼠中的肌肉生长和再生。 我们构建了这个U 54提案，其中包括一个总体项目和四个核心，以执行（1）药物化学;（2）药理学;（3）毒理学;和（4）潜在药物的疗效评估，以调节我们的四个目标。我们在高通量筛选（HTS）平台中使用了小分子基因表达调节（GEMS）技术，以鉴定调节我们靶点表达的小分子，这些靶点已在肌营养不良症动物模型中得到验证。我们已经通过HTS发现了多种化合物，这些化合物可以调节我们培养的肌肉细胞中的四个靶标。我们现在需要开始迭代过程，将这些最初的命中转化为药物。因此，这项研究提案的最终目标是鉴定、表征和优化可用于临床治疗肌营养不良症的小分子。

Description (provided by applicant): The purpose of this proposal is to develop new small molecule drugs for the treatment of Duchenne, and possibly other muscular dystrophies. We have chosen four targets that can alter the disease process if the protein levels are either increased or decreased. Our four targets are: utrophin (UTRN), myostatin (GDF8), the class la splice-form of insulin-like growth factor (IGF-la), and <x7-integrin (ITGA7). Work by others (and in some cases ourselves) has demonstrated that a modest increase in the levels of utrophin, IGF-la or ITGA7 can significantly improve the muscle weakness associated with mutations in the dystrophin and/or UTRN genes in mice. Similarly, inhibition of GDF8 has been shown to improve muscle growth and regeneration in mice harboring a mutation in the dystrophin gene (mdx) mice. We have constructed this U54 proposal with one overarching project and four cores to perform (1) medicinal chemistry; (2) pharmacology; (3) toxicology; and (4) efficacy assessment of potential drugs to modulate our four targets. We have used the Gene Expression Modulation by Small molecules (GEMS) technology in a high-throughput screening (HTS) platform to identify small molecules that modulate expression of our targets that have been validated in animal models of muscular dystrophy. We have discovered multiple compounds via the HTS that modulate our four targets in muscle cells in culture. We now need to begin the iterative process that will turn these initial hits into drugs. Thus, the ultimate goal of this research proposal is to identify, characterize and optimize small molecules that can be used in a clinical setting to treat muscular dystrophy.