Optimization of Novel Small Molecules to Antagonize FGF-23

拮抗 FGF-23 的新型小分子的优化

• 批准号: 10609883
• 负责人: Zhousheng Xiao
• 金额: $ 30.4万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609883
• 关键词: Affinity; Antibodies; Binding; Binding Proteins; Biological Assay; Biological Availability; Blocking Antibodies; Cardiotoxicity; Cardiovascular system; Cell model; Cells; Chemical Structure; Chronic Kidney Failure; Clinical Trials; Complex; Development; Disease; Disease model; Dose; Drug Kinetics; Drug Targeting; Early identification; Excretory function; Exhibits; FDA approved; FGF3 gene; FGFR1 gene; Familial hypophosphatemic bone disease; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Goals; Half-Life; HepG2; Homeostasis; Homologous Gene; Hormones; Human; Hypophosphatemia; In Vitro; Inherited; Isoenzymes; Kidney; Knockout Mice; Lead; Left Ventricular Hypertrophy; Ligands; Link; Liver Microsomes; Mediating; Metabolism; Molecular Conformation; Oral; Osteoblasts; Osteocytes; Osteomalacia; Outcome; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Play; Pre-Clinical Model; Process; Property; Proteins; Quality of life; Recombinant Fibroblast Growth Factor; Renal tubule structure; Reproducibility; Rickets; Risk; Role; Safety; Serum; Signal Transduction; Solubility; Specificity; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Titrations; Toxic effect; Validation; Vitamin D; absorption; analog; antagonist; autosome; bone; cytotoxicity; dentin matrix protein 1; design; drug candidate; efficacy testing; fibroblast growth factor 23; flexibility; genotoxicity; healing; high throughput screening; improved; in vitro testing; in vivo; inorganic phosphate; kidney cell; lead candidate; meter; mortality; mouse model; novel; novel strategies; overexpression; parenteral administration; pre-clinical; preclinical study; prevent; prototype; receptor; response; scaffold; screening; small molecule; small molecule therapeutics; therapeutic lead compound; tumor

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 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.

FGF-23是一种骨源性磷酸盐和维生素D调节激素，可激活FGFR/α-Klotho二元结构

项目成果

Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues.

• DOI: 10.1016/j.bmc.2020.115877
• 发表时间: 2021-01-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Downs RP;Xiao Z;Ikedionwu MO;Cleveland JW;Lin Chin A;Cafferty AE;Darryl Quarles L;Carrick JD
• 通讯作者: Carrick JD

Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.

• DOI: 10.1021/acs.jcim.2c00633
• 发表时间: 2022-08-08
• 期刊: JOURNAL OF CHEMICAL INFORMATION AND MODELING
• 影响因子: 5.6
• 作者: Liu, Shih-Hsien;Xiao, Zhousheng;Mishra, Sambit K.;Mitchell, Julie C.;Smith, Jeremy C.;Quarles, L. Darryl;Petridis, Loukas
• 通讯作者: Petridis, Loukas