Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities inHypmice

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that binds to binary FGFR/α-Klotho receptor complexes in the kidney tubules to inhibit phosphate reabsorption and 1,25(OH)2D production. Excess FGF23 causes X-linked hypophosphatemia (XLH) and tumor induced osteomalacia (TIO). Recently, Burosumab, an FGF23 blocking antibody, was approved for treating these hypophosphatemic disorders. A small molecule inhibitor that specifically binds to FGF23 to prevent activation of FGFR/α-Klotho complexes has potential advantages over a systemically administered FGF23 blocking antibody. We previously identified the small molecule ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a therapeutic lead FGF23 antagonist. Additional structure-activity studies developed a series of ZINC13407541 analogues with enhanced drug-like properties. In this study, we tested in a pre-clinicalHypmouse 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, and13a[(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] that exhibited increasedin vitropotency. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and significantly increased serum phosphate and 1,25(OH)2D concentrations inHypmice. Long-term parenteral treatment with8nor13aalso enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate inHypmice. The more potent13acompound showed greater therapeutic efficacy inHypmice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat FGF23-mediated disorders.