Optimization of Novel Small Molecules to Antagonize FGF-23

拮抗 FGF-23 的新型小分子的优化

基本信息

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
项目类别：
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

项目摘要

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是一种激活FGFR/α-Klotho二进制的骨源性磷酸盐和维生素D 肾脏中的复合体。循环FGF-23增加会导致X连锁（XLH）和常染色体隐性（ARH）低磷酸血症以及其他遗传性和获得性下降磷酸性疾病。自适应增加在FGF-23中，还在慢性肾脏疾病（CKD）中维持磷酸盐和维生素D稳态，并且是缔合的心血管（CV）死亡率增加。 KRN23，最近批准的FGF-23阻断抗体治疗XLH受到长期寿命的限制，需要全身给药，困难的剂量滴定和POTEN- tial到过度抑制FGF-23。由于潜在的毒性，KRN23未批准用于治疗升高的FGF-23 在CKD中。有机会开发钛，口服可生物利用，短效的小分子，以重新形成超出抑制FGF-23与FGFR/α-Klotho复合物的结合。我们的中心假设是一个小分子 FGF-23拮抗剂可以通过更灵活的剂量折点和更短的半衰期开发经过处理的次磷酸血症疾病，并可能扩大治疗指示，以防止FGF- 23 CKD中介导的CV并发症。使用基于计算，基于结构的高通量屏幕，我们识别曲解了治疗性铅化合物MD-3和几种类似物。我们的目标是将原型引线发展成一个临床前药物治疗由FGF-23引起的疾病的治疗超过。我们的具体目的是： 1）优化新型FGF-23拮抗剂的效力。我们将阐明结构活动关系（SAR）小分子FGF-23拮抗剂增加其效力。具有IC50 <500的几种化合物与在AIM2。2中检查的FGF阻滞抗体相比，ηm和％最大响应> 75％。进行体外抽象，分布，代谢和排泄（ADME），药代动力学（PK）和毒性屏幕。我们将执行早期体外ADME屏幕，以识别符合最佳阈值的化合物 - 老板（溶解度> 10 µm，在½> 30分钟的人肝微粒体中的稳定性，渗透率1.0 1E-6cm/s，蛋白质结合（血浆，人）<98％），其次是体外毒性/安全筛选，评估CYP抑制（5个主要同工酶的IC50> 10 µm），遗传毒性（AMES），心脏毒性（HERG结合IC50> 10 µm），cyto- 毒性（HEPG2，IC50> 100 µM）和脱靶效应。传递体外毒性筛查的化合物将前进到体内PK/暴露分析（T½> 60分钟）。 3）测试FGF-23的拮抗剂 FGF-23超过。我们选择2至3个FGF-23拮抗剂，这些拮抗剂符合最佳药物样特性并测试其能够治疗XLH和ARH的HYP和DMP1无效的临床前小鼠模型。我们还将确定FGF-23是否可以滴定拮抗剂，以防止CKD小鼠模型中的CV并发症，而不会引起诱导的助手 - 贫血。我们的预期结果是鉴定具有优势的小分子FGF-23拮抗剂超过当前的生物制剂。我们的影响是识别适合开发成新颖疗法的化合物遗传性下磷酸疾病，可能是一种与CKD拮抗FGF-23的新方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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