FGF-23 is a bone-derived phosphate and vitamin D regulating hormone that activates FGFR/?-Klotho binary complexes in the kidney. Increased circulating FGF-23 causes X-linked (XLH) and autosomal recessive (ARH) hypophosphatemia, as well as other hereditary and acquired hypophosphatemic disorders. Adaptive increases in FGF-23 also maintain phosphate and vitamin D homeostasis in chronic kidney disease (CKD) and is associ- ated with increased cardiovascular (CV) mortality. KRN23, a recently approved FGF-23 blocking antibody for treating XLH, is limited by a long half-life, need for systemic administration, difficult dose titration, and the poten- tial to over-suppress FGF-23. Due to potential toxicity, KRN23 is not approved for treatment of elevated FGF-23 in CKD. There is an opportunity to develop titratable, orally bioavailable, short-acting small molecules that re- versibly inhibit FGF-23 binding to FGFR/?-Klotho complexes. Our central hypothesis is that a small molecule FGF-23 antagonist can be developed with a more flexible dose-titration and shorter half-life that will be the pre- ferred treatment of hypophosphatemic disorders, and may expand the therapeutic indication to preventing FGF- 23 mediated CV complications in CKD. Using a computational, structure-based high-throughput screen, we iden- tified a therapeutic lead compound, MD-3 and several analogs. Our goal is to develop prototypic leads into a preclinical drug candidate for the treatment of disorders caused by FGF-23 excess.
Our Specific Aims are to: 1) Optimize the potency of novel FGF-23 antagonists. We will elucidate the structure-activity relationship (SAR) of small molecule FGF-23 antagonists to increase their potency. Several compounds with an IC50 < 500 ?M and % max response > 75% compared to an FGF-blocking antibody examined for druggability in Aim 2. 2) Perform in vitro absorption, distribution, metabolism and excretion (ADME), pharmacokinetic (PK) and toxicity screens. We will perform early in-vitro ADME screens to identify compounds that meet optimal thresh- olds (solubility > 10 M, stability in human liver microsomes with a t > 30 min, permeability 1.0 1E-6cm/s, protein binding (plasma, human) < 98%), followed by in-vitro toxicity/safety screens that evaluate CYP inhibition (IC50 > 10 M for 5 major isozymes), genotoxicity (AMES), cardiac toxicity (hERG binding IC50 > 10 M), cyto- toxicity (HepG2, IC50 > 100 M), and off-target effects. Compounds that pass the in-vitro toxicity screen will advance to in vivo PK/exposure profiling (t > 60 min). 3) Test FGF-23 antagonists in pre-clinical models of FGF-23 excess. We select 2 to 3 FGF-23 antagonists that meet the optimal drug-like properties and test their ability to treat Hyp and Dmp1 null pre-clinical mouse models of XLH and ARH. We will also determine if FGF-23 antagonists can be titrated to prevent CV complications in mouse models of CKD without inducing hyperphos- phatemia. Our expected outcomes are identification of small molecule FGF-23 antagonists with advantages over current biologicals. Our impact will be to identify compounds suitable for development into novel treatments of hereditary hypophosphatemic disorders, and possibly a new approach to antagonize FGF-23 in CKD.

Public Health Relevance

We are pursuing an early-stage preclinical validation of small molecule therapeutic leads that block FGF-23 interactions with the FGFR/?-Klotho complex to treat diseases of FGF-23 excess. We used an emerging computational technology based on FGF-23 structure and targetable conformations to identify prototypic therapeutic lead compounds that act as FGF-23 antagonists in target engagement assays, cell-based primary functional screens, ex vivo renal tubules, and proof-of-concept preclinical hypophosphatemic disease models. We propose an iterative process of lead compound development and optimization, from altering the chemical structure of our lead FGF-23 antagonist using medicinal chemistry to develop and test an improved, patentable lead compound with the goal of progressing to a preclinical drug candidate.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Gossett, Daniel Robert
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University of Tennessee Health Science Center
Internal Medicine/Medicine
Schools of Medicine
United States
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