Assay Development for Screening of Specific IKKalpha Kinase Inhibitors

筛选特定 IKKalpha 激酶抑制剂的测定方法开发

基本信息

  • 批准号:
    8182644
  • 负责人:
  • 金额:
    $ 19.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-01 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Although IKK1 and IKK2 are highly homologous, their functions are very unique. Specifically, IKK2 locates in the cytoplasm and functions through NF-kB pathways whereas IKK1 can translocate to and function in the nucleus that is independent of classical and alterative NF-kB pathways. Recent studies have demonstrated that IKK1 kinase plays a pivotal role in breast and prostate cancer development and cancer therapy resistance, suggesting that IKK1 kinase is an excellent target for cancer therapy. However, currently there are no IKK1 kinase-specific inhibitors or the methods for the discovery of IKK1 kinase-specific inhibitors available. In the proposed project we plan to develop a functional cell-based high-throughput screening (HTS) assay to identify specific inhibitors for IKK1 kinase. This assay utilizes the newly discovered function of nuclear IKK1 kinase that suppresses maspin transcription. We transfected human breast cancer cell line MCF7 with plasmid containing maspin promoter-driven luciferase reporter and established two stable reporter cell lines. These cell lines will be further characterized for HTS development. The density, incubation time, dimethyl sulfoxide (DMSO) concentration used to screen the IKK1 kinase specific inhibitors will also be optimized. In addition, we will establish a complementary assay and a series of counter-screen assays for the validation and prioritization of IKK1 kinase inhibitor candidates. Our studies will establish a high-selective and high-efficient functional cell- based HTS assay for the discovery of IKK1 kinase specific inhibitors. We will submit this assay to MLPCN when the project is completed. In our follow-up studies, promising candidates from screens will be examined further for their ability to inhibit IKK1 kinase activity, maspin expression, cell proliferation and/or motility in human breast and prostate cancer cell lines, and their ability to suppress breast and prostate cancer development, progression, metastasis, and therapy-resistance in animal models. PUBLIC HEALTH RELEVANCE: IKK1 kinase plays a pivotal role in breast and prostate cancer development and therapy-resistance, suggesting that IKK1 kinase is an excellent target for breast and prostate cancer treatment. However, currently there are no IKK1 kinase-specific inhibitors or the methods for the discovery of IKK1 kinase-specific inhibitors available. Our studies will establish a high-selective and high-efficient functional cell-based high-throughput screen system for the discovery of IKK1 kinase-specific inhibitors.
描述(申请人提供):虽然IKK1和IKK2高度同源,但它们的功能非常独特。具体来说,IKK2位于细胞质中,通过NF-kB途径发挥作用,而IKK1可以转运到细胞核中并在细胞核中发挥作用,而细胞核不依赖于经典的和可选的NF-kB途径。最近的研究表明,IKK1激酶在乳腺癌和前列腺癌的发展和癌症治疗耐药中起着关键作用,这表明IKK1激酶是癌症治疗的一个很好的靶点。然而,目前没有IKK1激酶特异性抑制剂,也没有发现IKK1激酶特异性抑制剂的方法。在拟议的项目中,我们计划开发一种基于功能细胞的高通量筛选(HTS)试验,以鉴定IKK1激酶的特异性抑制剂。该试验利用了新发现的核IKK1激酶抑制巨量蛋白转录的功能。我们用含有maspin启动子驱动荧光素酶报告基因的质粒转染人乳腺癌细胞株MCF7,建立了两个稳定的报告细胞株。这些细胞系将进一步表征HTS的发展。筛选IKK1激酶特异性抑制剂的密度、孵育时间、二甲基亚砜(DMSO)浓度也将进行优化。此外,我们将建立一个补充试验和一系列反筛选试验,以验证和确定IKK1激酶抑制剂候选物的优先级。我们的研究将为发现IKK1激酶特异性抑制剂建立一个高选择性和高效率的功能性细胞HTS实验。我们将在项目完成后将此分析提交给MLPCN。在我们的后续研究中,筛选的有希望的候选药物将进一步研究其抑制人类乳腺癌和前列腺癌细胞系中IKK1激酶活性、maspin表达、细胞增殖和/或运动的能力,以及它们在动物模型中抑制乳腺癌和前列腺癌发生、进展、转移和治疗耐药性的能力。

项目成果

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Jun-Li Luo其他文献

Jun-Li Luo的其他文献

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{{ truncateString('Jun-Li Luo', 18)}}的其他基金

Development of cancer therapeutic TBK1/IKKi dual inhibitors
癌症治疗TBK1/IKi双重抑制剂的开发
  • 批准号:
    9893827
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Development of cancer therapeutic TBK1/IKKi dual inhibitors
癌症治疗TBK1/IKi双重抑制剂的开发
  • 批准号:
    9248311
  • 财政年份:
    2016
  • 资助金额:
    $ 19.8万
  • 项目类别:
Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.
免疫炎症信号传导和激素难治性前列腺癌的演变。
  • 批准号:
    8637936
  • 财政年份:
    2011
  • 资助金额:
    $ 19.8万
  • 项目类别:
Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.
免疫炎症信号传导和激素难治性前列腺癌的演变。
  • 批准号:
    8235834
  • 财政年份:
    2011
  • 资助金额:
    $ 19.8万
  • 项目类别:
Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.
免疫炎症信号传导和激素难治性前列腺癌的演变。
  • 批准号:
    8042328
  • 财政年份:
    2011
  • 资助金额:
    $ 19.8万
  • 项目类别:
Immune-inflammatory signaling and hormone-refractory prostate cancer evolution.
免疫炎症信号传导和激素难治性前列腺癌的演变。
  • 批准号:
    8449737
  • 财政年份:
    2011
  • 资助金额:
    $ 19.8万
  • 项目类别:

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