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

Zhousheng Xiao, Demian Riccardi, Hector A. Velazquez, Ai L. Chin, Charles Yates, Jesse D. Carrick, Jeremy C. Smith, Jerome Baudry, Leigh Quarles

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of a-Klotho (a-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/a-KL complex. Additional modeling and functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/a-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited a-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.

Original languageEnglish (US)
Article numberra113
JournalScience Signaling
Volume9
Issue number455
DOIs
StatePublished - Nov 22 2016

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Hypophosphatemia
Kidney
Fibroblast Growth Factor Receptors
Vitamin D
Lead compounds
Rickets
Functional analysis
Vitamin D Deficiency
fibroblast growth factor 23
Chronic Renal Insufficiency
Metabolism
Screening
Bone
Chemical activation
Phosphates
Throughput
Bone and Bones

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia. / Xiao, Zhousheng; Riccardi, Demian; Velazquez, Hector A.; Chin, Ai L.; Yates, Charles; Carrick, Jesse D.; Smith, Jeremy C.; Baudry, Jerome; Quarles, Leigh.

In: Science Signaling, Vol. 9, No. 455, ra113, 22.11.2016.

Research output: Contribution to journalArticle

Xiao, Zhousheng ; Riccardi, Demian ; Velazquez, Hector A. ; Chin, Ai L. ; Yates, Charles ; Carrick, Jesse D. ; Smith, Jeremy C. ; Baudry, Jerome ; Quarles, Leigh. / A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia. In: Science Signaling. 2016 ; Vol. 9, No. 455.
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