PT  - JOURNAL ARTICLE
AU  - Zhousheng Xiao
AU  - Jiawang Liu
AU  - Shih-Hsien Liu
AU  - Loukas Petridis
AU  - Chun Cai
AU  - Li Cao
AU  - Guangwei Wang
AU  - Ai Lin Chin
AU  - Jacob W. Cleveland
AU  - Munachi O. Ikedionwu
AU  - Jesse D. Carrick
AU  - Jeremy C. Smith
AU  - L. Darryl Quarles
TI  - Small molecule FGF23 inhibitors increase serum phosphate and improve skeletal abnormalities in <em>Hyp</em> mice
AID  - 10.1101/2020.08.04.236877
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.04.236877
4099  - http://biorxiv.org/content/early/2020/08/05/2020.08.04.236877.short
4100  - http://biorxiv.org/content/early/2020/08/05/2020.08.04.236877.full
AB  - 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-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. 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 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 showed greater therapeutic efficacy in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat FGF23-mediated disorders.Competing Interest StatementThe authors have declared no competing interest.