| First Author | Xiao Z | Year | 2016 |
| Journal | Sci Signal | Volume | 9 |
| Issue | 455 | Pages | ra113 |
| PubMed ID | 27879395 | Mgi Jnum | J:260557 |
| Mgi Id | MGI:6140344 | Doi | 10.1126/scisignal.aaf5034 |
| Citation | Xiao Z, et al. (2016) A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia. Sci Signal 9(455):ra113 |
| abstractText | Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of alpha-Klotho (alpha-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/alpha-KL complex. Additional modeling and functional analysis found that Zinc13407541 bound to FGF-23 and disrupted its interaction with the FGFR1/alpha-KL complex; experiments in a heterologous cell expression system showed that Zinc13407541 selectivity inhibited alpha-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. |
