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Optimization of Novel Small Molecules to Antagonize FGF-23

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
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-01 至 2024-08-31
关键词:
AffinityAntibodiesBindingBinding ProteinsBiological AssayBiological AvailabilityBlocking AntibodiesCardiotoxicityCardiovascular systemCell modelCellsChemical StructureChronic Kidney FailureClinical TrialsComplexDevelopmentDiseaseDisease modelDoseDrug KineticsDrug TargetingEarly identificationExcretory functionExhibitsFDA approvedFGF3 geneFGFR1 geneFamilial hypophosphatemic bone diseaseFibroblast Growth FactorFibroblast Growth Factor ReceptorsGoalsHalf-LifeHepG2HomeostasisHomologous GeneHormonesHumanHypophosphatemiaIn VitroInheritedIsoenzymesKidneyKnockout MiceLeadLeft Ventricular HypertrophyLigandsLinkLiver MicrosomesMediatingMetabolismMolecular ConformationOralOsteoblastsOsteocytesOsteomalaciaOutcomePermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPlasmaPlayPre-Clinical ModelProcessPropertyProteinsQuality of lifeRecombinant Fibroblast Growth FactorRenal tubule structureReproducibilityRicketsRiskRoleSafetySerumSignal TransductionSolubilitySpecificityStructureStructure-Activity RelationshipTechnologyTestingTherapeuticTitrationsToxic effectValidationVitamin Dabsorptionanalogantagonistautosomebonecytotoxicitydentin matrix protein 1designdrug candidateefficacy testingfibroblast growth factor 23flexibilitygenotoxicityhealinghigh throughput screeningimprovedin vitro testingin vivoinorganic phosphatekidney celllead candidatemetermortalitymouse modelnovelnovel strategiesoverexpressionparenteral administrationpre-clinicalpreclinical studypreventprototypereceptorresponsescaffoldscreeningsmall moleculesmall molecule therapeuticstherapeutic lead compoundtumor

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中文摘要
翻译
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 肾脏中的复合物。循环FGF-23增加导致X连锁(XLH)和常染色体隐性遗传(ARH) 低磷酸盐血症以及其它遗传性和获得性低磷酸盐血症病症。适应性增长 在FGF-23中,也维持慢性肾病(CKD)中磷酸盐和维生素D稳态, 心血管(CV)死亡率增加。KRN 23,最近批准的FGF-23阻断抗体, 治疗XLH,受到半衰期长、需要全身给药、剂量滴定困难和潜在的 可能过度抑制FGF-23。由于潜在的毒性,KRN 23未被批准用于治疗升高的FGF-23 在CKD中。有机会开发可滴定的,口服生物可利用的,短效的小分子, 明显抑制FGF-23与FGFR/α-Klotho复合物的结合。我们的核心假设是一个小分子 FGF-23拮抗剂可以开发出更灵活的剂量滴定和更短的半衰期,这将是预治疗。 延迟治疗低磷酸盐血症疾病,并可能扩大治疗适应症,以防止FGF-2。 23例CKD介导的CV并发症。使用计算的,基于结构的高通量筛选,我们确定- 确定了治疗先导化合物MD-3和几种类似物。我们的目标是将原型线索发展成 用于治疗由FGF-23过量引起的病症的临床前候选药物。我们的具体目标是: 1)优化新型FGF-23拮抗剂的效力。我们将阐明构效关系 (SAR)小分子FGF-23拮抗剂,以增加其效力。IC 50 < 500的几种化合物 与在Aim 2中检查的可药用性的FGF阻断抗体相比,ηM和%最大响应> 75%。(二) 进行体外吸收、分布、代谢和排泄(ADME)、药代动力学(PK)和 毒性筛查我们将进行早期体外ADME筛选,以确定符合最佳阈值的化合物。 奥尔兹(溶解度> 10 µM,在人肝微粒体中的稳定性,t1/2> 30 min,渗透性1.0 1 E-6cm/s, 蛋白质结合(血浆,人)< 98%),随后进行体外毒性/安全性筛选, (IC50 5种主要同工酶> 10 µM)、遗传毒性(艾姆斯)、心脏毒性(hERG结合IC 50> 10 µM)、细胞毒性(hERG结合IC 50> 10 µM)。 毒性(HepG 2,IC 50> 100 µM)和脱靶效应。通过体外毒性筛选的化合物将 推进到体内PK/暴露曲线(t1/2> 60 min)。3)在临床前模型中测试FGF-23拮抗剂 FGF-23过量。我们选择了2至3种符合最佳药物样性质的FGF-23拮抗剂,并测试了它们的活性。 治疗Hyp和Dmp 1缺失的XLH和ARH临床前小鼠模型的能力。我们还将确定FGF-23是否 拮抗剂可滴定以预防CKD小鼠模型中的CV并发症,而不诱导高磷酸化。 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 超过了现有的生物制剂。我们的影响将是确定适合开发成新疗法的化合物 遗传性低磷酸盐血症疾病,并可能是一种新的方法,拮抗FGF-23在CKD。
英文摘要
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.
期刊论文(3)
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会议论文
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
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
Optimization of Novel Small Molecules to Antagonize FGF-23
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