Division of Nephrology, Department of Medicine, the University of Tennessee Health Science Center, Memphis,TN, 38165, USAUnited States
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This fibroblast growth factor-23 (FGF-23) has been found as a circulating hormone and pathogenic factor in many disease conditions. This review focuses on recent advances in FGF-23 as a therapeutic target, including fibroblast growth factor receptors (FGFR) tyrosine kinase inhibitor, FGF-23 antibody, FGF-23 C-terminal peptide, CYP24A1 inhibitor, and FGF-23 antagonist. We also update the advantages and disadvantages of targeting upstream and downstream molecules in FGF-23 signaling pathways.
Keywords: inhibitor; antagonist
ibroblast growth factor-23 (FGF-23) is a bone-derived hormone that inhibits phosphate reabsorption and 1,25-dihy- F 1,2 droxyvitamin D3 (1,25(OH)2D) production by the kidney (Figure 1). Physiologically, FGF-23 regulates systemic phosphate homeostasis and vitamin D metabolism through a bone-kidney 3,4 axis.3,4 However, excess FGF-23 in genetic disorders leads to hypophosphatemic rickets as well as may play a pathogenic role in adverse outcomes in chronic kidney disease.5-7 Primary increases in FGF-23 have been reported in rare hereditary hypophosphatemic disorders in humans and their mouse homologues,8-19 including X-linked hypophosphatemic rickets (XLH)/Hyp mice, caused by 14,15,20 inactivating mutations of Phex, autosomal recessive hypophosphatemic rickets 1 (ARHR1), caused by inactivating mutations of 15,20 10,14- Dmp1, ARHR2, caused by inactivating mutations in ENPP1, 17 and Raine Syndrome (RNS), caused by inactivation mutations 21,22 23-25 in FAM20C as well as tumor-induced osteomalacia (TIO). Secondary elevations of FGF-23 occurs in chronic kidney disease 1,26 (CKD).1,26 Elevated FGF-23 is initially an adaptive response to altered mineral metabolism in chronic kidney disease (CKD)27, but chronic elevations of FGF-23 are maladaptive and linked to in- 6 6,28-31 creased morbidity and mortality, cardiovascular disease, and 32,33 inflammation in CKD. Therefore, control of FGF-23 levels as well as its upstream and downstream signaling pathways could serve as a potential target to improve outcomes in many disease conditions. Currently, fibroblast growth factor receptors (FGFR) tyrosine kinase inhibitor (NVP-BGJ398), CYP24A1 inhibitor, 37,38 39,40 FGF-23 antibody (KRN23), FGF-23C-terminal peptide,
cc Copyright 2025 by Xiao Z. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited. and FGF-23 antagonist41 are being developed to treat disorders of excess FGF-23. This review will summarize recent advances in these areas.
Figure 1. FGF-23 Signaling in Renal Tubule Cells.FGF-23, FGFR, and α-Klotho (α- KL) form Ternary Complex to Activate FGFR Tyrosine Kinase Activity, Transduce FGF- 23 Signaling to Downstream Targeted Genes NPT2A, CYP27B1, and CYP24A1, and Regulate Renal Phosphorus Homeostasis and 1,25(OH)2D Metabolism 5-7 8-19
There is compelling evidence to support pharmacological inhibition of FGFRs in excess FGF-23. First, FGF-23 signaling is transduced by members of the FGF receptor (FGFRs, 1, 3, 4) 34,35 36 family in conjunction with the essential co-receptor Klotho, which confers tissue-specificity for endocrine FGF-23 signals owing to its
predominant expression in kidney (Figure 1).42 Second, hereditary hypophosphatemic disorders such as XLH/Hyp and ARHR1 involve activation of FGFR signaling and FGF-23 expression in osteocytes17 and osteocyte-specific deletion of Fgfr1 in Hyp mice markedly suppresses FGF-23 production.18 Third, a gainof-function mutation in FGFR1 causes osteoglophonic dysplasia (OGD), which is also associated with hypophosphatemia and elevated FGF-23 levels.43 Theoretically, it is useful to develop FGFR inhibitors that control FGF-23 signaling and production in disorders of excess FGF-23. In this regard, FGFR tyrosine kinase inhibitor (NVP-BGJ398) has been developed to treat FGF-23mediated hypophosphatemic diseases a and has been shown to block both the production and end-organ effects of FGF-23. However, NVP-BGJ398 is a small molecule with potent inhibitory activity of FGFRs 1, 3, and 4 and lacks selectivity for FGF-23/ FGFR/α-KL signaling, and their generalized ability to inhibit FGFRs in multiple tissues would have undesirable effects. In addition, a small molecule, SSR128129E (SSR), which binds to the extracellular part of FGFR, was reported to act as a FGFR 44,45 antagonist. So far, SSR128129E are being developed as antitumor drugs since these compounds have limitations, including specificity and potential toxicities. At present, there are no small molecules that specifically modulate FGF-23 activation of FGFR/ α-KL complexes. The discovery of such molecules would not only provide research tools to elucidate FGF-23 biological actions, but also would advance the discovery of new treatments based on this novel bone/kidney endocrine network.
A FGF-23 specific antibody [Burosumab, KRN23, Ultragenix (USA) and Kirin (Japan)] has been developed as a therapy for 37,38,46 XLH. KRN23 binds to and inhibits the biological activity of FGF-23. However, loss of FGF-23 function can have serious side effects, including hyperphosphatemia and soft-tissue calcifications. Indeed, preclinical studies in CKD models show that inhibiting FGF-23 with a high affinity blocking antibody increased mortality, 38 leading to no current plans to test KRN23 in CKD. Lowering FGF-23 in CKD is controversial, since use of calcimimetics to suppress PTH leads to modest reductions in FGF-23 and improved survival in patients with end-stage renal disease (ESRD).47 Since 30 million people or 15% of USA adults are estimated to have CKD and elevated FGF-23,48 identifying a drug to dose-dependently and reversibly reduce FGF-23 may improve CKD outcomes. To avoid toxicity, a low affinity FGF-23 blocking antibody (KRN23) was selected for clinical development. Clinical trials with KRN23 show efficacy to raise serum phosphate and improve rickets in 37,38 XLH. Although hyperphosphatemia occurred in ~6% of the KRN23 treated XLH patients, biologics such as KRN23 are plagued by high cost, the need for parenteral delivery, long half-life, and difficulty with dose titration. From the business perspective, there is an opportunity to develop a small, orally bioavailable small molecule to inhibit FGF-23.
Full-length FGF-23 is a 32-kDa protein that can be cleaved at 176RXXR179 site by a cellular endoproteasefur in, leading to the 42 13 22-kDa N-terminal and 16-kDa C-terminal fragments.13 Recent studies have shown that the C-terminal tail of FGF-23 (FGF-23C) can compete with full-length ligand for binding to the FGFR/α- KL complex, and hence can antagonize the phosphaturic activity of FGF-23 in vivo, both in healthy rats and in a mouse model of 39,40 phosphate wasting disorders. In order to increase the half-life of the FGF-23C peptide, the investigators generated a FGF-23C Fc fusion molecule and demonstrated that repeated injection of this molecule (twice a week, 10 mg/kg)selectively modulates the phosphate pathway via regulation of NPT2A expression in vivo by competitive antagonism of FGF-23 binding to the FGFR/α-KL co-receptor in Hypmice, a preclinical model of XLH.The unique 34,35 ability of FGF-23C Fc molecule to preferentially modulate the FGFR1/α-KL phosphate pathway but not FGFR3&4/α-KL in the control of 1,25(OH)2D levels in kidney makes this molecule ideal foruse as a new the rapeutic in the treatment of XLH, with 34,35 thepotential to significantly improve bone formation in XLH 39,40 patients with limited safety concerns.
FGF-23 impairs the production of renal 1,25(OH)2D through either inhibiting the expression of CYP27B1, the enzyme that converts 25-(OH)D to its active metabolite, or upregulating the expression of vitamin D 24-hydroxylase (CYP24A1), a mitochondrial enzyme responsible for inactivating vitamin D metabolites through the C-24 oxidation pathway.49 In the overexpressing mutant FGF23R176Q and Hyp mouse models, hypophosphatemic ricketswith high levels of FGF-23 are also associated with increased renal CYP24A1 expression, suggesting that elevated CYP24A1 activity is pivotal 50,51 to the pathophysiology of these disorders. Knockout of CYP24A1 in the Hyp and FGF23R176Q-transgenic miceresulted in near-complete recovery of rachitic bony abnormalities, but serum levels of phosphorus and 1,25(OH)2D did not improve in these murine models of human disease.36 Interestingly, treatment of Hyp and FGF23R176Q-transgenic mice with the CYP24A1 inhibitor CTA102 also ameliorated their rachitic bones.36 Whether pharmacologic inhibition of CYP24A1 activity goes solo as a therapeutic target remains to be further investigated.
In addition to FGF-23 specific antibody and FGF-23 C peptide, a computationally identified FGF-23 antagonist (ZINC13407541) was found to bind to FGF-23 that disrupts its interaction with the FGFR/α-KL complex in a heterologous cell expression system.41 This FGF-23 antagonist was also shown to inhibit FGF-23 signaling in isolated renal tubules ex vivo and to increase serum phosphate and 1,25(OH)2D in a mouse model of FGF- 23-related hypophosphatemic diseases.41 In addition, this FGF-23 antagonist slightly but significantly reduced FGF-23 levels along with increased PTH levels in mouse disease model.41 The findings of small molecule that antagonizes FGF-23 activation of FGFRs provide a new tool to probe the functions of FGF-23 and set the stage for developing clinical drug candidates to treat disorders of excess FGF-23. Furthermore FGF-23 antagonist can be costeffective, orally bioavailable and easily dose titration compared to the FGF-23 antibody. This small molecule has been using to
Table 1. GrSmall Molecules and Biologics in Treating Disorders of Excess FGF-23 FGFR Kinase Inhibi- Inhibition of FGFR tyrosine 34,35 tor kinase FGF-23 Antibody Function blocking FGF-23 C-terminal Competitive antagonism Peptides FGF-23 binding
CYP24A1 Inhibitor ity
FGF-23 Antagonist
develop lead compound for preclinical screening and late clinical trials.
As shown in Table 1, all of current FGF-23 targeted therapies have their advantages and disadvantages. The FGFR inhibitors show a strong inhibition of FGFR tyrosine kinase activity; these compounds can block both the production and end-organ effects of FGF-23, but demonstrate no specificity and potential tissue and organ toxicity. In contrast, FGF-23 antibody plays a function blocking on FGF-23and displays a high specificity of treatment. However, FGF-23 antibodyneeds parenteral delivery and high cost treatment. FGF-23 C-terminal peptides also have a high specificity of treatment, but the increased proteolytic instability during treatment would limit its use as a long-time therapeutic strategy. CYP24A1 inhibitor almost completely recover rachitic bone of hypophosphatemic disorder, but this compound has no effect on levels of phosphorus and 1,25(OH)2D. FGF-23 antagonist could be a promising therapeutic strategy because of effective, orally bioavailable and easily dose titration compared to the FGF-23 antibody. This small molecule has been using to develop lead compound for preclinical screening and late clinical trials.
As shown in Table 1, all of current FGF-23 targeted therapies have their advantages and disadvantages. The FGFR inhibitors show a strong inhibition of FGFR tyrosine kinase activity; these compounds can block both the production and end-organ effects of FGF-23, but demonstrate no specificity and potential tissue and organ toxicity. In contrast, FGF-23 antibody plays a function blocking on FGF-23and displays a high specificity of treatment. However, FGF-23 antibody needs parenteral delivery and high cost treatment. FGF-23 C-terminal peptides also have a high specificity of treatment, but the increased proteolytic instability during treatment would limit its use as a long-time therapeutic
Blocking both the production and end-organ effects of FGF- 23/no specificity High specificity of treatment and dose titratibility/Cost and 37,38 parenteral delivery High specificity of treatment/ of 39,40 the increased proteolytic instability during treatment Inhibition of CYP24A1 activ- Recovery of rachitic bone/no effect on levels of phosphorus 36 and 1,25(OH)2D Disruption of FGF-23 binding Orally bioavailable, dose titratibility, and cost-effective/Short 41 to FGFR/α-KL complex half-time
strategy.52 CYP24A1 inhibitor almost completely recover rachitic bone of hypophosphatemic disorder, but this compound has no effect on levels of phosphorus and 1,25(OH)2D. FGF-23 antagonist could be a promising therapeutic strategy because of its oral bioavailability, dose titratibility, and cost-effective if the optimization overcomes the short half time of the compound.
Fibroblast growth factor-23 is a circulating hormone that regulates phosphate and vitamin D metabolism. Excess actions of FGF-23 result in reductions in serum phosphate and 1,25(OH)2D levels and hypophosphatemi crickets. Therefore, it is necessary to develop therapeutic methods to suppress the activities of thathorm one. In fact, patients with hypophosphatemic disorders by FGF-23 excess were reported to benefit from FGF-23 blocking antibodies or 52 37,53,54 inhibitors of FGF-23 signaling. However, these therapies need careful monitoring dosing-use because deficient actions of FGF- 55,56 23 result in hyperphosphatemic disease. Indeed, management of FGF-23 levelsin patients with CKD seems to be debatable since modest reductions in FGF-23 with calcimimetics could improve survival in patients with ESRD,47 while inhibiting FGF-23 with a high affinity blocking antibody increased mortality in CKD,38 leading to questionable benefit from these novel therapies in CKD. However, use of either low affinity FGF-23 antibody or FGF-23 inhibitors to control FGF-23 excess actions remains a promising therapy for both hereditary and acquired hyperphosphatemic diseases.
The authors declare that they have no conflicts of interest.