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Diener, S. ; Schorpp, K.K. ; Strom, T.M. ; Hadian, K. ; Lorenz-Depiereux, B.

Development of a cell-based assay to identify small molecule inhibitors of FGF23 signaling.

Assay Drug Dev. Technol. 13, 476-487 (2015)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Fibroblast growth factor 23 (FGF23) is a key regulator of phosphate homeostasis. It is of crucial importance in hereditary and acquired hypo- and hyperphosphatemic disorders. Moreover, FGF23 has emerged as a promising biomarker for the prediction of adverse clinical outcomes in patients with chronic kidney disease (CKD), as it might be related to mortality, cardiovascular abnormalities and disease progression. FGF23 is a bone-derived endocrine factor, which inhibits renal tubular phosphate reabsorption by activating receptor complexes composed of FGF receptor (FGFR) 1c and the co-receptor Klotho. As a major signalling pathway mitogen-activated protein kinase (MAPK) pathway is employed. For the investigation of FGF23 in an in vitro model we established FGF23-inducible HEK293 cells that stably express Klotho (HEK293-KL). The induction of HEK293-KL cells by FGF23 was shown by detecting the activation of MAPK pathway, which could be reduced by the use of two known small-molecule inhibitors of MAPK pathway: SU5402 and U0126. To identify novel small-molecule compounds that modulate FGF23/FGFR1c/Klotho signalling, we have developed a cell-based reporter assay that is suited for high-throughput screening (HTS). The assay is based on the AlphaScreen SureFire platform of Perkin Elmer to monitor the phosphorylation of endogenous extracellular signal-regulated kinase 1 and 2 (ERK1/2) in cellular lysates of HEK293-KL after the induction with FGF23 in the presence of small-molecule compounds. Since increased plasma concentrations of FGF23 are the main cause of many phosphatemic disorders, a modulation of its effect could be a potential strategy for drug discovery and new therapeutic approaches in disorders affecting phosphate homeostasis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
ISSN (print) / ISBN 1540-658X
e-ISSN 1557-8127
Zeitschrift Assay and Drug Development Technologies
Quellenangaben Band: 13, Heft: 8, Seiten: 476-487 Artikelnummer: , Supplement: ,
Verlag Mary Ann Liebert
Verlagsort Larchmont, NY
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Molecular Toxicology and Pharmacology (TOX)