Development of small molecules for delaying the progression of muscular dystrophy

Duchenne肌营养不良症是一种毁灭性的X连锁疾病，大约每3000名男孩中就有一人受到影响，其特征是肌肉无力、失去行走能力以及最终导致呼吸和心脏并发症，导致这些年轻男子在十几岁或二十出头时死亡。这种罕见的肌肉萎缩疾病是无法治愈的。在为DMD患者寻找新疗法的持续努力中，我们正在使用一种名为GEMS(小分子基因表达调制)的专利药物发现平台技术(由PTC治疗公司开发)，以识别上调或下调蛋白质生产的小分子。事实证明，GEMS是一种非常强大的技术，可以解决困难的药物靶点。我们针对四个被认为与DMD的医学相关的靶点进行了高通量筛查。筛选出的化合物在基于细胞的分析中表现出足够的活性、选择性和效力，值得进一步表征和进行化学优化。先导优化是一个复杂的迭代过程，目的是精炼高温合成中确定的化学支架的结构，以提高化合物的活性、选择性和专一性以及它们的药物特性。目标 这一建议的目的是探索这些分子周围的化学空间，以评估这些分子的结构-活性关系(SAR)。合成孔径雷达是一系列给定化合物的化学结构与生物活性(体外和体内)和药理活性之间的关系。由生物学、化学、药理学和功效评估核心组成的四个核心小组已经组成，共同努力严格表征和优化调节四个目标中每一个的生产的化合物的生物、化学、药理和体内功效。 铅优化过程的目标是提高各类化学品的效力、选择性和药用性能，以便最终每个目标选择一种化合物进行毒理学测试，为人体研究做准备。这项工作的最终目标是确定至少两个开发候选药物，这些候选药物将在一系列研究中进行测试，以便能够向FDA提交至少两个IND(研究新药)申请。

Duchenne muscular dystrophy is a devastating, X-linked disease that affects approximately one in 3,000 boys and is characterized by muscle weakness, loss of ambulation and eventual respiratory and cardiac complications that result in the death of these young men in their late teens or early twenties. There is no cure for this rare muscle wasting disorder. In an ongoing effort to identify new treatments for DMD patients, we are using a proprietary drug discovery platform technology (developed by PTC Therapeutics) called GEMS (Gene Expression Modulation by Small-molecules) to identify small molecules that up- or down-regulate the production of proteins. GEMS has proven to be a very robust technology that can address difficult drug targets. We have performed high throughput screens against four targets believed to be medically relevant hi DMD. Compounds have emerged from the screen that demonstrate sufficient activity, selectivity and potency in cell-based assays to merit further characterization and chemical optimization. Lead optimization is a complex and iterative process of refining the structure of the chemical scaffolds identified hi HTS in order to improve the activity, selectivity and specificity of the compound as well as their drug characteristics. The aims of this proposal are to explore the chemical space surrounding these molecules to evaluate the structure-activity relationships (SAR) for these molecules. SAR is the relationship between chemical structure and biological (in vitro and in vivo) and pharmacological activity for a given series of compounds. Four Core groups consisting of Biology, Chemistry, Pharmacology and Efficacy Assessment Cores have been assembled to work in a concerted effort to rigorously characterize and optimize the biological, chemical, pharmacological and in vivo efficacy of the compounds that modulate production of each of the four targets. The objective of the lead optimization process is to increase potency, selectivity and pharmaceutical properties of the classes of chemicals such that ultimately a single compound per target is chosen to perform toxicology tests in preparation for studies in humans. The ultimate goal of this effort is to identify at least two Development Candidates that will be tested in a series of studies to enable submission of a minimum of two IND (Investigational New Drug) applications to the FDA.