Research ArticlePharmacology

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

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Science Signaling  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.


Fibroblast growth factor–23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets. Current therapeutics that target the receptor complex have limited utility clinically. Using a computationally driven, structure-based, ensemble docking and virtual high-throughput screening approach, we identified four novel compounds predicted to selectively inhibit FGF-23–induced activation of the FGFR/α-KL complex. Additional modeling and functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/α-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited α-KL–dependent FGF-23 signaling. Zinc13407541 also inhibited FGF-23 signaling in isolated renal tubules ex vivo and partially reversed the hypophosphatemic effects of excess FGF-23 in a mouse model. These chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.

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