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

描述：肌强直性营养不良1 （DM1）是成人肌肉营养不良的主要形式，导致进行性神经肌肉效应。这种疾病每6000人中就有1人患病。Nymirum感兴趣的是找到一种可以用来减缓或消除DM1进展的小分子。DM1的病因是DMPK基因中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剪接因子的活性，对正常细胞功能具有“毒性”。我们正在采取一种方法来识别小分子，这些小分子将与扩展的CUG RNA重复结合，以防止剪接因子的隔离，并修复细胞中异常的剪接声型。为此，我们确定了2个具有明确结构活性关系的小分子化学系列

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