The fibroblast growth factor (FGF) family and their signaling receptors are associated with multiple biological activities (proliferation, survival, apoptosis, differentiation, motility) that govern key processes (development, angiogenesis, and metabolism) for the growth and maintenance of organisms from worms to humans. 22 distinct FGFs have been identified, all sharing a conserved 120-aminoacids core domain with 15-65% sequence identity. FGF23 is a critical, bone-derived mediator of phosphate homeostasis, which functions in the kidney to regulate vitamin D biosynthesis and renal absorption of phosphate. In kidney proximal tubule epithelial cells, FGF23 signaling controls expression of the vitamin D metabolizing enzymes CYP27B1 and CYP24A1, resulting in decreased biosynthesis and elevated turnover of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). In addition, FGF23 impairs expression of the sodium-phosphate co-transporters NPT2A and NPT2C in the brush border membrane of proximal tubular cells, which mediate the re-absorption of urinary phosphate.
Excess levels or augmented function of FGF23 result in hypophosphatemia along with impaired biosynthesis of 1,25(OH)2D3(vitamin D) and are associated with several hereditary hypophosphatemia disorders with skeletal abnormalities as a consequence of impaired bone mineralization, including X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR). In addition, in rare cases secretion of FGF23 by tumor cells has been identified to cause hypophosphatemia resulting in tumor-induced osteomalacia (TIO). Elevated levels of FGF23 are also commonly observed in post-renal transplantation patients leading to servere hypophosphatemia. FGF23 plays a role in several other hypophosphatemic syndromes such as epidermal nevus syndrome, osteoglophonic dysplasia and McCune-Albright syndrome which have been associated with increased FGF23 levels. XLH and other FGF23-mediated hypophosphatemia diseases such as ADHR and ARHR commonly manifest clinically in early childhood with short stature and bowing deformities of the legs.
Current therapeutic approaches to these diseases are mainly limited to dietary vitamin D and phosphate supplementation. Although therapy improves growth and rickets in patients, correction is often limited and results in impaired post-pubertal height. Depending on the severity of disease, but owing to the persistence of FGF23 signaling—constituting a continuous counteractive force—administration of high doses of phosphate and vitamin D are often required for medical therapy of XLH and other FGF23-related hypophosphatemia diseases, necessitating close monitoring and dose adjustments to avoid toxicity risks such as abdominal pain and diarrhea or secondary hyperparathyroidism, hypercalcemia and ectopic calcifications.
Hence, there is a need for a reliable and efficacious medication for the treatment of the aforementioned disfiguring ailments and directly targeting pathological FGF23 signaling by blocking FGFR signal transduction might provide an advantageous therapeutic approach over the current standard of treatment.