A drug based approach for integrin-mediated alleviation for muscular dystrophy

基于药物的整合素介导缓解肌营养不良症的方法

• 批准号: 10006285
• 负责人: Juan Marugan
• 金额: $ 25.03万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10006285
• 关键词: Actins; Agonist; Chemicals; Complex; Computer Simulation; Cytoskeleton; Disease Progression; Docking; Duchenne muscular dystrophy; Dystrophin; Enhancers; Extracellular Matrix; Family; Gastrointestinal Stromal Tumors; Gene Expression; Genes; Genetic Transcription; Glycoproteins; Goals; ITGA7 gene; Integrins; Laminin; Lead; Link; Mediating; Modification; Muscle; Muscle Cells; Muscular Dystrophies; Myocardium; Myopathy; Patients; Pharmaceutical Preparations; Production; Proteins; Receptor Protein-Tyrosine Kinases; Renal Cell Carcinoma; Resistance; SU11248; Sarcolemma; Skeletal Muscle; Study models; Testing; Tyrosine Kinase Inhibitor; base; computer studies; disease-causing mutation; laminin A; member; protein complex; receptor; scaffold; shear stress; small molecule; small molecule inhibitor

The current goal of the project is the chemical modification of the active lead molecule Sunitinib, with the aim of reducing the molecules anti-proliferative activity, while mantaining its agonist activity towards the production of 7 integrin gene expression. Sunitinib is a receptor tyrosine kinase inhibitor small molecule, approved for use in both renal cell carcinoma and gastrointestinal stromal tumors. Sunitinib is a molecule belonging to the same scaffold family as the original HTS hit molecule identified by NCATS, SU9516. During this period, docking and modeling studies were performed to select the most adequate place in the scaffold of the lead molecule to perform modifications. Several molecules were synthesized to test the hypothesis of the modelling/computational studies regarding the selective activity towards the production of integrin, while reducing the anti-proliferative activity. The synthesized molecules are awaiting testing.

该项目当前的目标是对活性先导分子舒尼替尼进行化学修饰，目的是降低该分子的抗增殖活性，同时保持其对 7 整合素基因表达产生的激动剂活性。舒尼替尼是一种受体酪氨酸激酶抑制剂小分子，被批准用于肾细胞癌和胃肠道间质瘤。舒尼替尼是与 NCATS 鉴定的原始 HTS 命中分子 SU9516 属于同一支架家族的分子。 在此期间，进行了对接和建模研究，以选择先导分子支架中最合适的位置来进行修饰。合成了几种分子来测试关于整合素产生的选择性活性同时降低抗增殖活性的建模/计算研究的假设。合成的分子正在等待测试。