Screens for Novel Agonists/Antagonists of Endocrine Fibroblast Growth Factors

描述（由申请人提供）：Agave BioSystems和德克萨斯大学西南医学中心的Makoto Kuro-o教授正在提议合作筛选新的小分子，作为Klotho和Klotho依赖性内分泌成纤维细胞生长因子的激动剂或拮抗剂。该I期研究的预期结果将是验证高通量筛选方法，并确定调节内分泌成纤维细胞生长因子FGF21和FGF23活性的已确认的靶点。每次撞击的效果将在FGF特异性的基于细胞的检测中得到证实，验证成纤维细胞生长因子已知活性的变化。第一阶段的小规模“概念验证”筛选活动将在第二阶段进行更大规模的活动，确定一系列新的激动剂和拮抗剂，为这种新型内分泌成纤维细胞生长因子效应器提供更广泛的结构和作用机制。选定的靶点将进行早期靶点到先导的优化，并在小动物试验之前评估细胞毒性。将治疗啮齿动物疾病模型，并验证内分泌FGF活性调节的预期分子，细胞和生理变化。这个治疗靶点验证的转化研究项目将导致潜在的针对慢性肾脏疾病、糖尿病、肥胖和癌症的新药的开发。

DESCRIPTION (provided by applicant): Agave BioSystems and Professor Makoto Kuro-o at the University of Texas Southwestern Medical Center are proposing a collaborative effort to screen for novel small molecules acting as agonists or antagonists of the Klotho and Klotho- dependent endocrine Fibroblast Growth Factors. The expected outcome of this Phase I effort will be the validation of a high-throughput screening methodology and the identification of confirmed hits which modulate the activity of endocrine Fibroblast Growth Factors FGF21 and FGF23. The effect of each hit will be confirmed in FGF- specific cell-based assays verifying changes in known activities of the Fibroblast Growth Factors. The small scale "proof of concept" screening campaign of the Phase I will be followed by a larger campaign in the Phase II do identify series of novel agonists and antagonists offering to uncover a broader set of structures and mechanisms of action for this novel effectors of endocrine Fibroblast Growth Factors. Selected hits will undergo early hit-to-lead optimization and be evaluated for cytotoxicity prior t small animal testing. Rodent disease models will be treated and the expected molecular, cellular and physiological changes of endocrine FGF activity modulation will be verified. This translational research project for therapeutic target validation will lead to the development of potential new drugs against chronic kidney disease, diabetes, obesity and cancer.