Selective Fyn kinase inhibitors for 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在全球范围内已达到流行病的比例。虽然肥胖和T2D的分子机制不断取得进展，但安全有效的治疗方式的鉴定和开发受到极大限制。迫切需要创新药物来对抗肥胖和糖尿病。最近的数据沿着我们的初步数据有力地表明，Fyn激酶的药物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方法。在初步的高通量筛选中，我们已经确定了一个有前途的选择性Fyn激酶抑制剂。该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。这将包括基于新型化学的SAR、基于人体细胞的葡萄糖和脂肪酸代谢测定中的表征以及以潜在作用机制为中心的生化测定。 公共卫生相关性：代谢性疾病，如2型糖尿病、肥胖症及其相关的合并症，在全世界已达到流行病的程度。迫切需要创新药物来对抗肥胖和糖尿病。该提案的重点是进一步开发和鉴定用于治疗代谢性疾病的先导小分子药物。

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.