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Novel small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities in Hyp mice

Journal Article · · Molecular Pharmacology
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  1. Univ. of Tennessee, Knoxville, TN (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Tennessee Technological Univ., Cookeville, TN (United States)
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We report that excess fibroblast growth factor 23 (FGF23) causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the FGFR/a-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23. Additional structure-activity studies developed a series of ZINC13407541 analogues with enhanced drug-like properties. In this study, we tested in a pre-clinical Hyp mouse homologue of XLH a direct connect analogue (8n) [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] that exhibited the greatest stability in microsomal assays, and 13a [(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] that exhibited increased in vitro potency. Using cryo-electron microscopy (Cryo-EM) structure and computational docking, we identified a key binding residue (Q156) of the FGF23 antagonists, ZINC13407541 and its analogues (8n and 13a) in the N-terminal domain of FGF23 protein. Site-directed mutagenesis and bimolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assay confirmed the binding site of these three antagonists. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and increased serum phosphate and 1,25(OH)2D concentrations in Hyp mice. Long-term parenteral treatment with 8n or 13a also enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate in Hyp mice. The more potent 13a compound had greater therapeutic effects in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat excess FGF23-mediated disorders.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
National Institutes of Health; USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1860586
Journal Information:
Molecular Pharmacology, Journal Name: Molecular Pharmacology Journal Issue: 4 Vol. 101; ISSN 0026-895X
Publisher:
American Society for Pharmacology and Experimental TherapeuticsCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

60 APPLIED LIFE SCIENCES
Computational drug design
FGF
discovery
drug development
fibroblast growth factor
molecular modeling
signal transduction inhibitors