Research ArticlePharmacology

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia

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Sci. Signal.  22 Nov 2016:
Vol. 9, Issue 455, pp. ra113
DOI: 10.1126/scisignal.aaf5034

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Ligand-targeted therapy for hypophosphatemia

Patients with excess fibroblast growth factor–23 (FGF-23) in their circulation have metabolic deficiencies that contribute to chronic kidney disease and the bone-softening disorder rickets. The pharmacokinetics of the available molecules that target the FGF-23 receptor complex limit clinical applicability. Xiao et al. used computationally based screening to identify a compound predicted to bind the ligand, not the receptor. When tested experimentally, the compound was selective for FGF-23 compared to other FGF family ligands and prevented FGF signaling in cultured kidney cells and isolated renal tubules. The compound reduced the serum concentration of FGF-23 and raised the serum concentration of phosphorus, vitamin D, and parathyroid hormone in a mouse model of excess FGF-23. Thus, this approach of targeting the ligand, rather than the receptor, may be a new therapeutic option for hypophosphatemic patients.