P3: The Structure, Function, and Pharmacologic inhibition of FGF23

Yale University, New Haven CT

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Abstract

FGFs mediate their biological responses by binding to and activating a family of receptor tyrosine kinases[unreadable] (RTKs) consisting of four gene products designated FGFR1-FGFR4. FGFR 1-3 have two isoforms produced[unreadable] by alternate splicing which differ in their ligand-binding specificities and tissue expression patterns.[unreadable] FGF23 is the largest of the 22 known FGFs and differs from others by its unique extended C-terminal[unreadable] domain. X-linked hypophosphatemic rickets (XLH) patients have elevated circulating levels of FGF23, and[unreadable] heterozygous mutations within a protease recognition site in the FGF23 gene cause a syndrome that[unreadable] phenocopies XLH, autosomal dominant hypophosphatemic rickets (ADHR). In ADHR, resistance to[unreadable] proteolytic cleavage of the FGF23 molecule presumably leads to delayed clearance and accumulation in the[unreadable] circulation. Furthermore, tumor induced osteomalacia (TIO), another disorder with a similar phenotype to[unreadable] XLH, has been found to be caused in many cases by tumor overproduction of FGF23 as a paraneoplastic[unreadable] syndrome. Finally, recessive mutations resulting in low intact circulating FGF23 levels cause tumoral[unreadable] calcinosis (TC), an unusual disorder in which serum P levels are elevated. Thus these clinical observations[unreadable] have ascribed a novel role for FGFs, and FGF23 in particular, in phosphate homeostasis. However, little is[unreadable] known about the mode of action of FGF23, and the potential for translating new information from exploring[unreadable] these pathways to human diseases is great.[unreadable] Thus, the overall goals of this project are (1) To determine the cell signaling function of FGF23 via FGF[unreadable] receptors, (2) To determine the atomic structure of FGF23, (3) To explore the receptor specificity of FGF23[unreadable] using murine models deficient in specific FGFR isoforms, (4) To generate new mouse models to explore the[unreadable] biological function of FGF23 in normal and disease conditions, and (5) To develop new pharmacological[unreadable] approaches using small molecule inhibitors of FGFR tyrosine kinase domain for the treatment of diseases[unreadable] caused by abnormal FGF23 function. Our goals will be accomplished by applying genetic, biochemical,[unreadable] structural and cell biological approaches, in the setting of a model human disease in which to carry forward[unreadable] subsequent translational application.