title: A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia.
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.
authors.affiliation: Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38165, USA.
authors.forename: Zhousheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Chemistry, Earlham College, 801 National Road West, Richmond, IN 47374, USA.|Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Demian
authors.initials: D
authors.lastname: Riccardi
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.|Department of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville, TN 38501, USA.
authors.forename: Hector A
authors.initials: HA
authors.lastname: Velazquez
authors.affiliation: University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN 37830, USA.
authors.forename: Ai L
authors.initials: AL
authors.lastname: Chin
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yates
authors.affiliation: University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, TN 37830, USA.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Carrick
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.|Department of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville, TN 38501, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.|Department of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville, TN 38501, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Baudry
authors.affiliation: Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38165, USA. dquarles@uthsc.edu.
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017674:Hypophosphatemia / Q000188:drug therapy / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D056004:Molecular Dynamics Simulation; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23