Development of Targeted Drugs for Osteoporosis
骨质疏松症靶向药物的开发
基本信息
- 批准号:9894758
- 负责人:
- 金额:$ 27.73万
- 依托单位:
- 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:2019-03-15 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlbers-Schonberg diseaseAntibodiesBindingBiological AssayBiological ProductsBiologyBone ResorptionBone Resorption InhibitionBone necrosisCell Differentiation processCellsCytoplasmic TailDataDeteriorationDevelopmentDiseaseDrug KineticsDrug TargetingExploratory/Developmental GrantFailureFeasibility StudiesFemoral FracturesFoundationsFutureGenesGoalsImmuneImmune systemImmunologistIn VitroInfectionInjectionsIntravenousJawKnock-in MouseLigandsMAP Kinase GeneMAPK Signaling Pathway PathwayMacrophage Colony-Stimulating FactorMacrophage Colony-Stimulating Factor ReceptorMediatingMethodsMusMutationOralOsteoclastsOsteogenesisOsteoporosisOutcomeOvariectomyPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPostmenopausal OsteoporosisPropertyPublic HealthPublishingResearchResearch Project GrantsRiskRoleRouteSafetySignal PathwaySkeletonStudy modelsSystemTRANCE proteinTestingTherapeuticThymic epithelial cellTreatment EfficacyWorkanalogbasebonebone fragilitybone lossbone masscostdesigndrug discoveryexperiencefracture riskhigh throughput screeningimmune system functionimprovedin vivoinfection riskintraperitonealmacrophagemonocytemouse modelnew therapeutic targetnovelpreventprogrammed cell death protein 1receptorside effectsmall moleculesubcutaneoussuccesstherapeutic targettherapy outcome
项目摘要
Project Summary
Osteoporosis is a common disease characterized by low bone mass and microarchitectural deterioration of the
skeleton, resulting in bone fragility and increased risks for fractures. Osteoporosis is caused by an imbalance
between bone resorption and bone formation in favor of bone resorption. Thus, effective inhibition of bone
resorption has long been recognized as an important therapeutic strategy for osteoporosis. Osteoclasts, the
bone resorbing cell, differentiate from cells of the monocyte/macrophage lineage upon stimulation by M-CSF
and RANKL. RANKL exerts these diverse functions by binding and activating its receptor RANK. Mice lacking
the gene for either RANKL or RANK develop osteopetrosis due to complete failure to form osteoclast,
indicating that the RANKL/RANK system is essential for osteoclast formation. Thus, RANKL was recognized as
an attractive antiresorptive drug target for osteoporosis shortly after its discovery and Amgen subsequently
developed a humanized anti-RANKL antibody (denosumab) for treating postmenopausal osteoporosis.
However, denosumab causes several side effects such as osteonecrosis of the jaw (ONJ), increased risk of
serious infections and atypical femur fractures. In particular, ONJ and increased infection risks are likely due to
the suppressing effect of denosumab on the immune system since RANKL regulates immune cell
development, function and survival. Also, as a biological agent, the cost of denosumab is high and the method
of delivery (injection) is not ideal. Thus, a better targeting strategy would be to use small molecules to target
RANK signaling pathways that are involved in osteoclast formation but not in the immune system function. We
previously identified two motifs in the RANK cytoplasmic domain that regulate osteoclast formation in vitro. To
assess the role of the two RANK motifs in osteoclast formation in vivo, we have generated knockin (KI) mice
bearing inactivating mutations in the two RANK motifs. Osteoclast formation is dramatically reduced in the KI
mice, confirming the role of these two motifs in osteoclast formation in vivo. Importantly, inactivation of these
two motifs does not affect the ability of RANK to activate the signaling pathways (NF-κB and MAPK) known to
mediate immune cell development and function. Hence, we hypothesize that specifically targeting these two
RANK motifs has the potential to serve as effective and selective therapeutic targets for osteoporosis. Our
ultimate goal is to develop efficacious and safe small molecule drugs targeting the two RANK motifs for
osteoporosis. To this end, we have developed cell-based assays for identifying compounds targeting the two
RANK motifs. High throughput screens of 200,000 compounds with the cell-based assay systems followed by
counter screen assays have identified several compounds that potently inhibited osteoclast formation without
affecting the activation of NF-κB and MAPK pathways in vitro. This proposal seeks to carry out important proof-
of-concept studies to assess the conceptual and technical feasibility of this novel therapeutic targeting strategy.
项目概要
骨质疏松症是一种常见疾病,其特征是骨量低下和骨骼微结构恶化
骨骼,导致骨骼脆弱并增加骨折风险,这是由不平衡引起的。
骨吸收和骨形成之间的关系,有利于骨吸收,从而有效抑制骨形成。
骨吸收长期以来被认为是骨质疏松症的重要治疗策略。
骨吸收细胞,在 M-CSF 刺激下从单核细胞/巨噬细胞系细胞分化
RANKL 通过结合和激活其缺乏 RANK 的受体来发挥这些不同的功能。
RANKL 或 RANK 基因由于完全无法形成破骨细胞而发生骨硬化症,
表明 RANKL/RANK 系统对于破骨细胞的形成至关重要,因此,RANKL 被认为是
发现后不久,它就成为治疗骨质疏松症的一个有吸引力的抗骨吸收药物靶点,随后安进公司也随之而来
开发了一种人源化抗 RANKL 抗体(地诺塞麦)用于治疗绝经后骨质疏松症。
然而,狄诺塞麦会引起多种副作用,例如颌骨坏死 (ONJ)、增加以下风险:
严重感染和非典型股骨骨折特别是 ONJ 和感染风险增加可能是由于。
由于 RANKL 调节免疫细胞,狄诺塞麦对免疫系统的抑制作用
此外,作为生物制剂,狄诺塞麦的成本很高,而且方法也很复杂。
因此,更好的靶向策略是使用小分子来靶向。
RANK 信号通路参与破骨细胞形成,但不参与免疫系统功能。
先前在 RANK 细胞质结构域中发现了两个在体外调节破骨细胞形成的基序。
为了评估两个 RANK 基序在体内破骨细胞形成中的作用,我们生成了敲入 (KI) 小鼠
KI 中两个 RANK 基序的失活突变显着减少了破骨细胞的形成。
小鼠,证实了这两个基序在体内破骨细胞形成中的作用,重要的是,这些基序的失活。
两个基序不影响 RANK 激活已知信号通路(NF-κB 和 MAPK)的能力
因此,我们专门针对这两种细胞进行研究。
RANK 基序有潜力成为骨质疏松症的有效和选择性治疗靶点。
最终目标是开发针对这两个 RANK 基序的有效且安全的小分子药物
为此,我们开发了基于细胞的检测方法来识别针对这两种疾病的化合物。
使用基于细胞的测定系统对 200,000 种化合物进行高通量筛选,然后进行
反筛选试验已经鉴定出几种能够有效抑制破骨细胞形成的化合物,而无需
影响 NF-κB 和 MAPK 通路的体外激活 该提案旨在进行重要的证明-
概念研究旨在评估这种新型治疗靶向策略的概念和技术可行性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('XU FENG', 18)}}的其他基金
Cell-Based Assays for Identifying Anti-RANK Signaling Agents
用于识别抗 RANK 信号转导剂的细胞测定法
- 批准号:
7426192 - 财政年份:2007
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation and Function
破骨细胞分化和功能中的 RANK 信号转导
- 批准号:
7270519 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation and Function
破骨细胞分化和功能中的 RANK 信号转导
- 批准号:
7914254 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation and Function
破骨细胞分化和功能中的 RANK 信号转导
- 批准号:
7424166 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation & Function
破骨细胞分化中的 RANK 信号转导
- 批准号:
6789959 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation & Function
破骨细胞分化中的 RANK 信号传导
- 批准号:
6533019 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation & Function
破骨细胞分化中的 RANK 信号转导
- 批准号:
6646595 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation and Function
破骨细胞分化和功能中的 RANK 信号转导
- 批准号:
7146856 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation & Function
破骨细胞分化中的 RANK 信号传导
- 批准号:
6436676 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
RANK Signaling in Osteoclast Differentiation and Function
破骨细胞分化和功能中的 RANK 信号转导
- 批准号:
7473237 - 财政年份:2001
- 资助金额:
$ 27.73万 - 项目类别:
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