Screens for Novel Agonists/Antagonists of Endocrine Fibroblast Growth Factors

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 Iwill 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. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: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 antagonists of the Klotho-dependent endocrine Fibroblast Growth Factor FGF23 and as agonists of the Klotho-dependent FGF21. The identification of such compounds will be used for therapeutic target validation and potentially lead to the development of novel drugs against chronic kidney disease, diabetes, obesity and aging.