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

描述：强直性肌营养不良 1 (DM1) 是成人肌营养不良的主要形式，可导致进行性神经肌肉效应。这种疾病影响六千分之一的人。 Nymirum 有兴趣识别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 序列的扩展。这种重复RNA通过隔离和改变正常神经肌肉功能所需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来鉴定与扩展的 CUG RNA 重复序列结合的小分子，以防止剪接因子的隔离并修复细胞中异常的剪接表型。为此我们鉴定了2个化学系列的小分子，具有清晰的结构活性关系 用于 DM1 细胞模型中的 CUG RNA 结合和异常剪接的修复。在这个提案中，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，并将其应用于靶向药物化学。 DM1 代表了一项未满足的重大医疗需求，患者需要新药来减缓或消除神经肌肉恶化

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