Targeted Small Molecule Medicinal Chemistry for Myotonic Dystrophy-1 Drug Develop

描述：强直性肌营养不良症1（DM1）是导致进行性神经肌肉效应的成人肌营养不良症的主要形式。这种疾病影响6000人中的1人。Nymirum有兴趣确定一种可用于减缓或消除DM1进展的小分子。DM1的原因是DMPK基因内CUG RNA序列的扩增。这种重复RNA通过隔离和改变正常神经肌肉功能所需的剪接因子的活性而对正常细胞功能具有“毒性”。我们正在采取一种方法，以确定小分子，将结合到扩展的CUG RNA重复，以防止螯合的剪接因子和修复异常剪接的细胞中的表型。为此，我们已经确定了2个化学系列的小分子，具有明确的结构活性关系 用于DM1细胞模型中的CUG RNA结合和异常剪接的拯救。在这个提议中，我们的目标是优化该系列的结构特征，以找到更有效的结合剂和剪接救援分子。为此，我们将利用我们与RNA结构和小分子相互作用相关的广泛知识和工具，并将其用于靶向药物化学。DM 1代表了一个主要的未满足的医疗需求，患者需要新的药物来减缓或消除神经肌肉退化

DESCRIPTION: Myotonic dystrophy 1 (DM1) is the leading form of adult muscular dystrophy resulting in progressive neuromuscular effects. The disease affects 1 in 6000 people. Nymirum is interested in identifying a small molecule that can be used to slow or eliminate the progression of DM1. The cause of DM1 is the expansion of a CUG RNA sequence within the DMPK gene. This repeat RNA is "toxic" to normal cellular function by sequestering and altering the activity of needed splicing factors for normal neuromuscular function. We are taking an approach to identify small molecules that will bind to the expanded CUG RNA repeat to prevent sequestration of splicing factors and repair the abnormal splicing phonotype in cells. To this end we have identified 2 chemical series of small molecules with clear structure activity relationships for CUG RNA binding and rescue of abnormal splicing in a DM1 cell model. In this proposal, we aim to optimize the structural features of the series to find more potent binders and splicing rescue molecules. To do this we will utilize our extensive knowledge and tools related to RNA structure and small molecule interactions and bring it to bear on targeted medicinal chemistry. DM1 represents a major unmet medical need and patients are in need of new drugs to slow or eliminate the neuromuscular deterioration