A Computationally Identified Compound Antagonizes Excess FGF-23 Signaling in Renal Tubules and a Mouse Model of Hypophosphatemia

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2016 Nov 24

PMID 27879395

Citations 18

Authors

Zhousheng Xiao

Demian Riccardi

Hector A Velazquez

Ai L Chin

Charles R Yates

Jesse D Carrick

Jeremy C Smith

Jerome Baudry

L Darryl Quarles

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.

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