Selective Fyn kinase inhibitors for treatment of metabolic disease

用于治疗代谢疾病的选择性 Fyn 激酶抑制剂

• 批准号: 8200674
• 负责人: Bentley Cheatham
• 金额: $ 35.07万
• 依托单位: ZEN-BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8200674
• 关键词: Adipocytes; Animal Model; Biochemical; Biological Assay; Cells; Chemistry; Comorbidity; Data; Development; Diabetes Mellitus; Diet; Drug Kinetics; End Point Assay; Epidemic; Evaluation; Glucose; Human; In Vitro; Inhibitory Concentration 50; Intervention; Lead; Medicine; Metabolic; Metabolic Diseases; Modality; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Play; Relative (related person); Rodent Model; Role; STK11 gene; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Validation; analog; base; cell mediated immune response; combat; design; enzyme substrate; fatty acid metabolism; fatty acid oxidation; glucose metabolism; high throughput screening; in vivo Model; inhibitor/antagonist; innovation; insulin sensitivity; kinase inhibitor; lipid metabolism; next generation; novel; novel strategies; pre-clinical; process optimization; small molecule

DESCRIPTION (provided by applicant): Metabolic diseases such as type 2 diabetes (T2D), obesity and their related co-morbidities have reached epidemic proportions worldwide. While progress continues to be made into the molecular mechanisms involved in both obesity and T2D, the identification and development of safe, efficacious therapeutic modalities is significantly limited. There is an urgent need for innovative medicines to combat both obesity and diabetes. Recent data along with our preliminary data strongly suggest that pharmacological intervention of Fyn kinase provides an excellent target and novel approach for the discovery of new drugs to treat metabolic disease. In preliminary high throughput screens we have identified a promising selective inhibitor of Fyn kinase. This proposal describes an approach for further development and identification of additional analogs of our lead compound. This will include SAR based on novel chemistries, characterization in human cell-based assays for glucose and fatty acid metabolism as well as biochemical assays centered on potential mechanism of action. PUBLIC HEALTH RELEVANCE: Metabolic diseases such as type 2 diabetes, obesity and their related co-morbidities have reached epidemic proportions worldwide. There is an urgent need for innovative medicines to combat both obesity and diabetes. This proposal focuses on further development and identification of lead small molecule drug for the treatment of metabolic disease.

描述（由申请人提供）：代谢性疾病，如2型糖尿病（T2D）、肥胖及其相关合并症已在全球范围内达到流行程度。虽然肥胖症和T2D的分子机制研究不断取得进展，但安全、有效的治疗方式的确定和发展仍显着有限。现在迫切需要创新药物来对抗肥胖和糖尿病。最近的数据和我们的初步数据强烈表明，Fyn激酶的药理干预为发现治疗代谢性疾病的新药提供了一个很好的靶点和新的途径。在初步的高通量筛选中，我们已经确定了一种有前途的Fyn激酶选择性抑制剂。本提案描述了进一步开发和鉴定我们的先导化合物的其他类似物的方法。这将包括基于新化学的SAR，基于人类细胞的葡萄糖和脂肪酸代谢分析的表征，以及以潜在作用机制为中心的生化分析。