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: 8258211
• 负责人: LUCIO COMAI
• 金额: $ 24.48万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258211
• 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. PUBLIC HEALTH RELEVANCE: We have developed a HTS screen to identify compounds that alter the biology of toxic CUGexp RNAs in myotonic dystrophy 1 (DM1). This screen will be used to identify therapeutic compounds that can be used to treat DM1.

描述（由申请人提供）：肌发育症（DM1）是人类最常见的成年发作性肌营养不良症。目前，尚无治愈方法或FDA批准的DM1和相关疾病的药物。 DM1是一种常染色体显性疾病，是由于DMPK基因的3'未翻译区域中CTG重复序列的扩展而产生的。这种缺陷导致编码膨胀的CUG重复序列（CugeXP）的突变型DMPK RNA表达，该突变体形成了大型核内RNA-蛋白质复合物或焦点。 CugeXP RNA的表达导致异常RNA剪接，这又与DM1病理学的关键特征的发展有关。我们假设在DM1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反向DM1病理学。为了检验这一假设，我们开发了主要的HTS和二级验证测定法，以鉴定有选择地改变DMPK Cugexp RNA生物学的小分子而不会影响正常的DMPK转录本。我们的室内图书馆是使用强大的机器学习化学信息学平台开发的，由40,000个高度多样的小分子组成，代表数百万种化合物的库。从2500种化合物的筛选中获得的初步结果表明，我们的策略允许快速鉴定有效的分子，这些分子在患者细胞和DM1小鼠模型中成功逆转DM1病理。为了确定可以作为DM1的治疗性鸡尾酒开发的一组有效的铅化合物，我们提出了以下目的：AIM1。实施主要HTS和二级命中验证测定法，以从我们的内部图书馆筛选20,000个分子。 AIM 2。基于DM1患者细胞的测试中的测试命中，以鉴定逆转五个键的细胞DM1表型的高效铅。铅的选择性，毒性和协同作用将平行测量。 AIM 3。将重申铅化合物的化学结构，以优化药理特性并建立结构活性关系。 公共卫生相关性：我们已经开发了HTS筛选，以识别改变肌营养不良1（DM1）中有毒CugeXP RNA的生物学的化合物。该屏幕将用于识别可用于治疗DM1的治疗化合物。