Screens for Novel Agonists/Antagonists of Endocrine Fibroblast Growth Factors

描述（由申请人提供）：龙舌兰生物系统公司和得克萨斯大学西南医学中心的Makoto Kuro-o教授提出了一项合作努力，以筛选作为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的新型小分子。这一I期工作的预期结果将是高通量筛选方法的验证和调节内分泌成纤维细胞生长因子FGF 21和FGF 23活性的确认命中的鉴定。将在FGF特异性细胞试验中确认每次命中的效果，以验证成纤维细胞生长因子已知活性的变化。在I期的小规模“概念验证”筛选活动之后，将在II期进行更大规模的活动，确定一系列新型激动剂和拮抗剂，以揭示这种内分泌成纤维细胞生长因子的新型效应物的更广泛的结构和作用机制。选定的命中将进行早期命中-电极导线优化，并在小动物试验之前评价细胞毒性。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。这个用于治疗靶点验证的转化研究项目将导致开发针对慢性肾脏疾病，糖尿病，肥胖和癌症的潜在新药。

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.