# Optimization of Novel Small Molecules to Antagonize FGF-23 > **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $304,000 ## Abstract FGF-23 is a bone-derived phosphate and vitamin D regulating hormone that activates FGFR/α-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/α-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 ηM 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 µM, stability in human liver microsomes with a t ½ > 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 µM for 5 major isozymes), genotoxicity (AMES), cardiac toxicity (hERG binding IC50 > 10 µM), cyto- toxicity (HepG2, IC50 > 100 µM), and off-target effects. Compounds that pass the in-vitro toxicity screen will advance to in vivo PK/exposure profiling (t ½ > 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 ... ## Key facts - **NIH application ID:** 10129375 - **Project number:** 5R01DK121132-03 - **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR - **Principal Investigator:** L DARRYL QUARLES - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $304,000 - **Award type:** 5 - **Project period:** 2019-07-01 → 2024-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10129375 ## Citation > US National Institutes of Health, RePORTER application 10129375, Optimization of Novel Small Molecules to Antagonize FGF-23 (5R01DK121132-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129375. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*