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

描述：强直性肌营养不良症1(DM1)是成人肌营养不良症的主要形式，导致进行性神经肌肉效应。这种疾病每6000人中就有1人受到影响。Nymirum感兴趣的是识别一种小分子，可以用来减缓或消除DM1的进展。DM1的原因是DMPK基因内CUG RNA序列的扩展。这种重复的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，对正常的细胞功能产生“毒性”。我们正在采取一种方法来识别将与扩展的CUG RNA重复序列结合的小分子，以防止剪接因子的隔离，并修复细胞中的异常剪接音型。为此，我们鉴定了两个具有明确构效关系的小分子化学系列 用于CUG RNA结合和挽救DM1细胞模型中的异常剪接。在这项建议中，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，我们将利用我们在RNA结构和小分子相互作用方面的广泛知识和工具，将其应用于靶向药物化学。DM1代表着一种主要的未得到满足的医疗需求，患者需要新的药物来减缓或消除神经肌肉的恶化

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