In Vivo Study of of Chemokine Antagonists for Cancer

癌症趋化因子拮抗剂的体内研究

基本信息

  • 批准号:
    8829202
  • 负责人:
  • 金额:
    $ 16.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-04-01 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Metastatic breast cancer kills patients. Our research is focused on developing a novel therapeutic platform to stop the progression of metastatic breast cancer. There is considerable evidence for the involvement of chemokines in metastatic tumor cell disease spreading. We have discovered novel small molecule CX3CR1 antagonists that target CX3CR1 in tumor cells and have shown that this chemokine receptor is involved in metastasis. This proposal aims to evaluate chemokine mediated dissemination as a novel therapeutic approach to halt the homing, arrest, and extravasation of circulating tumor cells to the bone marrow. We have demonstrated target proof of concept in Fractalkine knock-out animals and by treatment with a neutralizing antibody directed toward CX3CR1 expressed on cancer cells in animal models of metastasis by showing a significant decrease in disseminated tumor cells to the skeleton. Targeting an inflammatory chemokine such as Fractalkine as opposed to a homeostatic chemokine is predicted to provide a safe mechanism of action. Both CX3CR1 and Fractalkine knock-out animals are viable and appear normal compared to wild type animals which suggests that CX3CR1 antagonism will be a relatively benign intervention. This approach will provide non- cytotoxic drugs against a novel molecular target, the chemokine receptor CX3CR1, to stop the progression of metastatic breast cancer. The target, CX3CR1, is over expressed in malignant tissue and on highly metastatic tumor cells, including those responsible for inflammatory breast cancer (IBC). IBC is a very aggressive metastatic disease in need of new approaches. In addition to IBC, the successful development of agents which slow or halt metastasis are envisioned to have broad beneficial use. We will develop proprietary small molecule CX3CR1 antagonists which target highly metastatic tumor cells. A CX3CR1 neutralizing monoclonal antibody and drug conjugate approaches are likely as follow-on products. Specific Aims of this proposal are: Aim 1: To scale up the synthesis of JMS-17-2 for preliminary evaluation in our in vivo model, and optimize the lead compounds, JMS-16-7 and JMS-17-2, to improve selectivity and drug-like properties such as; water solubility, plasma and liver microsomal stability, and microsomal intrinsic clearance. Aim 2: To determine the pharmacokinetic properties of our best CX3CR1 antagonist meeting potency and ADME criteria for water solubility, plasma stability, intrinsic clearance, and plasma protein binding by pharmacokinetic determination in the mouse, and to test this candidate in our translational animal models of metastasis.
描述(由申请人提供):转移性乳腺癌会导致患者死亡。我们的研究重点是开发一种新的治疗平台,以阻止转移性乳腺癌的进展。有相当多的证据表明趋化因子参与转移性肿瘤细胞疾病的扩散。我们已经发现了靶向肿瘤细胞中CX 3CR 1的新型小分子CX 3CR 1拮抗剂,并表明这种趋化因子受体参与转移。该提案旨在评估趋化因子介导的传播作为一种新的治疗方法,以阻止循环肿瘤细胞的归巢,逮捕和外渗到骨髓。我们已经在Fractalkine基因敲除动物中证明了概念的靶向证明,并且通过在转移的动物模型中用针对癌细胞上表达的CX 3CR 1的中和抗体治疗,通过显示向骨骼的播散的肿瘤细胞的显著减少。预测靶向炎性趋化因子如Fractalkine而不是稳态趋化因子提供安全的作用机制。与野生型动物相比,CX 3CR 1和Fractalkine敲除动物都是存活的并且表现正常,这表明CX 3CR 1拮抗作用将是相对良性的干预。这种方法将提供针对新型分子靶点趋化因子受体CX 3CR 1的非细胞毒性药物,以阻止转移性乳腺癌的进展。靶点CX 3CR 1在恶性组织和高转移性肿瘤细胞中过度表达,包括那些导致炎性乳腺癌(IBC)的细胞。IBC是一种非常侵袭性的转移性疾病,需要新的方法。除了IBC之外,预期减缓或停止转移的药剂的成功开发具有广泛的有益用途。我们将开发针对高转移性肿瘤细胞的专有小分子CX 3CR 1拮抗剂。CX 3CR 1中和单克隆抗体和药物偶联物方法可能作为后续产品。本提案的具体目的是:目的1:扩大JMS-17-2的合成,以在我们的体内模型中进行初步评估,并优化先导化合物JMS-16-7和JMS-17-2,以改善选择性和药物样性质,例如:水溶性、血浆和肝微粒体稳定性以及微粒体固有清除率。目标二:通过在小鼠中进行药代动力学测定,确定我们最佳CX 3CR 1拮抗剂的药代动力学特性,该拮抗剂符合水溶性、血浆稳定性、固有清除率和血浆蛋白结合率的效价和ADME标准,并在转移的转化动物模型中测试该候选药物。

项目成果

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Joseph M Salvino其他文献

Joseph M Salvino的其他文献

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{{ truncateString('Joseph M Salvino', 18)}}的其他基金

Chemical Probes and Drug Discovery
化学探针和药物发现
  • 批准号:
    10627694
  • 财政年份:
    2023
  • 资助金额:
    $ 16.8万
  • 项目类别:
Purchase of an Echo 650 acoustic liquid handler with Access workstation
购买带有 Access 工作站的 Echo 650 声学液体处理机
  • 批准号:
    10176267
  • 财政年份:
    2021
  • 资助金额:
    $ 16.8万
  • 项目类别:
In Vivo Study of of Chemokine Antagonists for Cancer
癌症趋化因子拮抗剂的体内研究
  • 批准号:
    8690420
  • 财政年份:
    2014
  • 资助金额:
    $ 16.8万
  • 项目类别:
A NOVEL SMALL MOLECULE CX3CR1 ANTAGONIST HALTS METASTASIS
一种新型小分子 CX3CR1 拮抗剂可阻止转移
  • 批准号:
    9340341
  • 财政年份:
    2014
  • 资助金额:
    $ 16.8万
  • 项目类别:
Molecular Screening and Protein Expression Shared Resource
分子筛选和蛋白质表达共享资源
  • 批准号:
    10570944
  • 财政年份:
    1997
  • 资助金额:
    $ 16.8万
  • 项目类别:
Molecular Screening and Protein Expression Shared Resource
分子筛选和蛋白质表达共享资源
  • 批准号:
    10360641
  • 财政年份:
    1997
  • 资助金额:
    $ 16.8万
  • 项目类别:
Molecular Screening and Protein Expression Shared Resource
分子筛选和蛋白质表达共享资源
  • 批准号:
    9917711
  • 财政年份:
  • 资助金额:
    $ 16.8万
  • 项目类别:

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