Identification of Therapeutic Small Molecules for Myotonic Dystrophy Type 1

1 型强直性肌营养不良治疗小分子的鉴定

• 批准号: 8695714
• 负责人: LUCIO COMAI
• 金额: $ 1.57万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695714
• 关键词: 3' Untranslated Regions; Adult; Affect; Biological Assay; Biology; Cells; Chemical Structure; Defect; Development; Disease; FDA approved; Genes; Housing; Human; Lead; Libraries; Link; Machine Learning; Measures; Muscular Dystrophies; Myoblasts; Myotonic Dystrophy; Nuclear RNA; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Property; Protein Kinase C Alpha; RNA; RNA Splicing; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Transcript; Validation; base; mouse model; mutant; protein complex; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Myotonic dystrophy (DM1) is the most common adult onset muscular dystrophy in humans. Currently, there is no cure or an FDA approved drug for DM1 and related diseases. DM1 is an autosomal dominant disorder resulting from the expansion of a CTG-repeat sequence in the 3' untranslated region of the DMPK gene. This defect results in the expression of mutant DMPK RNAs encoding expanded CUG repeats (CUGexp) that form large intra nuclear RNA-protein complexes or foci. Expression of CUGexp RNAs leads to abnormal RNA splicing, which in turn has been linked to the development of key features of DM1 pathology. We hypothesize that small molecules that degrade or disperse CUGexp RNAs in DM1 cells can re-establish normal splice patterns and reverse DM1 pathology. To test this hypothesis, we have developed a primary HTS and a secondary hit validation assay to identify small-molecules that selectively alter the biology of DMPK CUGexp RNAs without affecting the normal DMPK transcripts. Our in house library was developed using a robust machine learning chemoinformatics platform and consists of 40,000 highly diverse small-molecules representing a library of several million compounds. Preliminary results obtained from a screen of 2,500 compounds demonstrate that our strategy allows the rapid identification of potent molecules that successfully reverse DM1 pathology in both patient cells and DM1 mouse models. In a concerted effort to identify a set of potent lead compounds that can be developed as a therapeutic cocktail for DM1 we propose the following Aims: Aim 1. Implement primary HTS and the secondary hit validation assay to screen 20,000 molecules from our in-house library. Aim 2. Test hits in tertiary DM1 patient cell-based assays to identify highly potent leads that reverse five key cellular DM1 phenotypes. Selectivity, toxicity and synergy of leads will be measured in parallel. Aim 3. The chemical structure of lead compounds will be reiteratively refined to optimize pharmacological properties and establish structure-activity relationships.

描述（由申请人提供）：强直性肌营养不良症（DM 1）是人类最常见的成人型肌营养不良症。目前，没有治愈或FDA批准的药物用于DM 1和相关疾病。DM 1是由DMPK基因3'非翻译区CTG重复序列扩增引起的常染色体显性遗传病。这种缺陷导致编码扩展的CUG重复序列（CUGexp）的突变体DMPK RNA的表达，所述CUG重复序列形成大的核内RNA-蛋白质复合物或病灶。CUGexp RNA的表达导致异常的RNA剪接，这反过来又与DM 1病理学的关键特征的发展有关。我们假设，在DM 1细胞中降解或分散CUGexp RNA的小分子可以重新建立正常的剪接模式并逆转DM 1病理。为了验证这一假设，我们开发了一种初级HTS和二级命中验证试验，以鉴定选择性改变DMPK CUGexp RNA生物学而不影响正常DMPK转录物的小分子。我们的内部库是使用强大的机器学习化学信息学平台开发的，由40，000种高度多样化的小分子组成，代表了数百万种化合物的库。从2,500种化合物的筛选中获得的初步结果表明，我们的策略可以快速鉴定出在患者细胞和DM 1小鼠模型中成功逆转DM 1病理的有效分子。在一致努力，以确定一组有效的先导化合物，可以开发为治疗鸡尾酒DM 1，我们提出了以下目标：目标1。实施初级HTS和次级命中验证分析，从我们的内部库中筛选20，000个分子。目标二。在三级DM 1患者基于细胞的测定中进行测试命中，以鉴定逆转五种关键细胞DM 1表型的高效先导物。将平行测量电极导线的选择性、毒性和协同作用。目标3。先导化合物的化学结构将被粘附性地精制以优化药理学性质并建立结构-活性关系。