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 R.; Carrick, Jesse D.; Smith, Jeremy C.; Baudry, Jerome; Quarles, L. Darryl

doi:10.1126/scisignal.aaf5034

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

Journal Article · Tue Nov 22 00:00:00 EST 2016 · Science Signaling

DOI:https://doi.org/10.1126/scisignal.aaf5034· OSTI ID:1335368

Xiao, Zhousheng ^[1]; Riccardi, Demian ^[2]; Velazquez, Hector A. ^[3]; Chin, Ai L. ^[4]; Yates, Charles R. ^[5]; Carrick, Jesse D. ^[4]; Smith, Jeremy C. ^[3]; Baudry, Jerome ^[3]; Quarles, L. Darryl ^[1]

Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Medicine
Earlham College, Richmond, IN (United States). Dept. of Chemistry; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology
Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics
Tennessee Technological Univ., Cookeville, TN (United States). Dept. of Chemistry
Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Pharmaceutical Sciences

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. In this paper, 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. Finally, these chemical probes provide a platform to develop lead compounds to treat disorders caused by excess FGF-23.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee Health Science Center, Memphis, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)

Sponsoring Organization:: USDOE

Contributing Organization:: Tennessee Technological Univ., Cookeville, TN (United States)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1335368

Journal Information:: Science Signaling, Vol. 9, Issue 455; ISSN 1945-0877

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 20 works

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Targeting Fibroblast Growth Factor 23 Signaling with Antibodies and Inhibitors, Is There a Rationale? Fukumoto, Seiji Frontiers in Endocrinology, Vol. 9 https://doi.org/10.3389/fendo.2018.00048	journal	February 2018
Role of Fibroblast Growth Factor-23 in Innate Immune Responses Fitzpatrick, Elizabeth A.; Han, Xiaobin; Xiao, Zhousheng Frontiers in Endocrinology, Vol. 9 https://doi.org/10.3389/fendo.2018.00320	journal	June 2018
X-Linked Hypophosphatemia and FGF23-Related Hypophosphatemic Diseases: Prospect for New Treatment Kinoshita, Yuka; Fukumoto, Seiji Endocrine Reviews, Vol. 39, Issue 3 https://doi.org/10.1210/er.2017-00220	journal	January 2018

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