skip to main content

DOE PAGESDOE PAGES

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

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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [4] ;  [3] ;  [3] ;  [1]
  1. Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Medicine
  2. Earlham College, Richmond, IN (United States). Dept. of Chemistry; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology
  3. 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
  4. Tennessee Technological Univ., Cookeville, TN (United States). Dept. of Chemistry
  5. Univ. of Tennessee Health Science Center, Memphis, TN (United States). Dept. of Pharmaceutical Sciences
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
Science Signaling
Additional Journal Information:
Journal Volume: 9; Journal Issue: 455; Journal ID: ISSN 1945-0877
Publisher:
AAAS
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee Health Science Center, Memphis, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Sponsoring Org:
USDOE
Contributing Orgs:
Tennessee Technological Univ., Cookeville, TN (United States)
Country of Publication:
United States
Language:
English
Subject:
97 MATHEMATICS AND COMPUTING; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1335368