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    Monitoring gene silencing and annotating gene function in living cells
    1.
    发明申请
    Monitoring gene silencing and annotating gene function in living cells 审中-公开
    监测基因沉默和注释活细胞中的基因功能

    公开(公告)号：US20120208197A1

    公开(公告)日：2012-08-16

    申请号：US13137605

    申请日：2011-08-29

    申请人： Stephen William Watson Michnick ,  Barbara Belisle ,  Marnie L. MacDonald ,  John K. Westwick ,  Jane Elizabeth Lamerdin

    发明人： Stephen William Watson Michnick ,  Barbara Belisle ,  Marnie L. MacDonald ,  John K. Westwick ,  Jane Elizabeth Lamerdin

    IPC分类号： C12Q1/68 ,  G01N33/573 ,  G01N33/566

    CPC分类号： G01N33/502 ,  C12Q1/6897 ,  G01N33/5008 ,  G01N33/5041

    摘要： The cell-based assays described in the present invention can be used to directly assess the sensitivity and specificity of the gene annotation reagent against its target, mapping genes and to determine if a non-targeted gene participates in a pathway of interest or is functionally linked to another gene or protein. Preferred assay embodiments include fluorescence or luminescence assays in intact (live or fixed) cells. Such fluorescence or luminescence assays include high-throughput or high-content assays for protein activity, subcellular localization, post-translational modifications, or interactions of proteins. Suitable assays may include protein-protein interaction assays; protein translocation assays; and post-translational modification assays. The invention can be used to assess the efficacy of any gene silencing experiment, and to map novel genes into biochemical pathways, and to identify novel pharmaceutical targets. The results also demonstrate the feasibility of employing this strategy in genome-wide functional annotation efforts.

    摘要翻译： 本发明中描述的基于细胞的测定可用于直接评估基因注释试剂对其靶标，测绘基因的灵敏度和特异性，并确定非靶向基因是否参与感兴趣的途径或功能上相关 到另一种基因或蛋白质。 优选的测定实施方案包括在完整（活的或固定的）细胞中的荧光或发光测定。 这种荧光或发光测定法包括用于蛋白质活性，亚细胞定位，翻译后修饰或蛋白质相互作用的高通量或高含量测定。 合适的测定可以包括蛋白质 - 蛋白质相互作用测定; 蛋白质易位测定; 和翻译后修饰测定。 本发明可用于评估任何基因沉默实验的功效，并将新基因映射到生物化学途径中，并鉴定新的药物靶点。 结果还表明在全基因组功能注释方面采用这一策略的可行性。

    Protein fragment complementation assays for high-throughput and high-content screening
    3.
    发明授权
    Protein fragment complementation assays for high-throughput and high-content screening 失效
    用于高通量和高含量筛选的蛋白质片段互补测定

    公开(公告)号：US07935493B2

    公开(公告)日：2011-05-03

    申请号：US11450379

    申请日：2006-06-12

    申请人： Stephen William Watson Michnick ,  Ingrid Remy ,  Marnie MacDonald ,  Jane Lamerdin ,  Helen Yu ,  John K. Westwick

    发明人： Stephen William Watson Michnick ,  Ingrid Remy ,  Marnie MacDonald ,  Jane Lamerdin ,  Helen Yu ,  John K. Westwick

    IPC分类号： G01N33/53 ,  G01N33/532 ,  G01N33/533 ,  G01N33/573 ,  G01N21/00 ,  G01N21/76 ,  C07K14/00

    CPC分类号： G01N33/5011 ,  G01N33/5008 ,  G01N33/5041 ,  G01N33/542 ,  G01N33/6845 ,  G01N2500/02 ,  Y02A90/26

    摘要： The present invention provides protein fragment complementation assays for drug discovery, in particular to identify compounds that activate or inhibit cellular pathways. Based on the selection of an interacting protein pair combined with an appropriate PCA reporter, the assays may be run in high-throughput or high-content mode and may be used in automated screening of libraries of compounds. The interacting pair may be selected by cDNA library screening; by gene-by-gene interaction mapping; or by prior knowledge of a pathway. Fluorescent and luminescent assays can be constructed using the methods provided herein. The selection of suitable PCA reporters for high-throughput or high-content (high-context) assay formats is described for a diversity of reporters, with particular detail provided for examples of monomeric enzymes and fluorescent proteins. Methods are described for constructing such assays for one or more steps in a biochemical pathway; testing the effects of compounds from combinatorial, natural product, peptide, antibody, nucleic acid or other diverse libraries on the protein or pathway(s) of interest; and using the results of the screening to identify specific compounds that activate or inhibit the protein or pathway(s) of interest. Single-color and multi-color assays are disclosed. Further disclosed are universal expression vectors with cassettes that allow the rapid construction of assays for a large and diverse number of gene/reporter combinations. The development of such assays is shown to be straightforward, providing for a broad, flexible and biologically relevant platform for drug discovery.

    摘要翻译： 本发明提供用于药物发现的蛋白质片段互补测定法，特别是鉴定激活或抑制细胞途径的化合物。 基于与适当的PCA报道子组合的相互作用的蛋白质对的选择，测定可以以高通量或高含量模式进行，并且可以用于化合物文库的自动化筛选。 可以通过cDNA文库筛选来选择相互作用的对; 通过基因相互作用作图; 或通过路径的先验知识。 可以使用本文提供的方法构建荧光和发光测定。 针对多种报道者描述了适合于高通量或高含量（高上下文）测定形式的PCA报告人的选择，具体提供了单体酶和荧光蛋白的实例。 描述了用于构建生物化学途径中的一个或多个步骤的这种测定方法; 测试来自组合，天然产物，肽，抗体，核酸或其他不同文库的化合物对感兴趣的蛋白质或途径的影响; 并使用筛选结果来鉴定激活或抑制感兴趣的蛋白质或途径的特定化合物。 公开了单色和多色测定。 进一步公开的是具有盒的通用表达载体，其允许快速构建用于大量和多样化数量的基因/报道子组合的测定。 显示出这种测定的发展是直接的，为药物发现提供了广泛，灵活和生物学上相关的平台。

    Protein fragment complementation assays for high-throughput and high-content screening
    5.
    发明申请
    Protein fragment complementation assays for high-throughput and high-content screening 审中-公开
    用于高通量和高含量筛选的蛋白质片段互补测定

    公开(公告)号：US20120149597A1

    公开(公告)日：2012-06-14

    申请号：US13067007

    申请日：2011-05-02

    申请人： Stephen William Watson Michnick ,  Ingrid Remy ,  Marnie MacDonald ,  Jane Lamerdin ,  Helen Yu ,  John K. Westwick

    发明人： Stephen William Watson Michnick ,  Ingrid Remy ,  Marnie MacDonald ,  Jane Lamerdin ,  Helen Yu ,  John K. Westwick

    IPC分类号： C40B30/06 ,  C40B40/10

    CPC分类号： G01N33/5011 ,  G01N33/5008 ,  G01N33/5041 ,  G01N33/542 ,  G01N33/6845 ,  G01N2500/02 ,  Y02A90/26

    摘要： The present invention provides protein fragment complementation assays for drug discovery, in particular to identify compounds that activate or inhibit cellular pathways. Based on the selection of an interacting protein pair combined with an appropriate PCA reporter, the assays may be run in high-throughput or high-content mode and may be used in automated screening of libraries of compounds. The interacting pair may be selected by cDNA library screening; by gene-by-gene interaction mapping; or by prior knowledge of a pathway. Fluorescent and luminescent assays can be constructed using the methods provided herein. The selection of suitable PCA reporters for high-throughput or high-content (high-context) assay formats is described for a diversity of reporters, with particular detail provided for examples of monomeric enzymes and fluorescent proteins. Methods are described for constructing such assays for one or more steps in a biochemical pathway; testing the effects of compounds from combinatorial, natural product, peptide, antibody, nucleic acid or other diverse libraries on the protein or pathway(s) of interest; and using the results of the screening to identify specific compounds that activate or inhibit the protein or pathway(s) of interest. Single-color and multi-color assays are disclosed. Further disclosed are universal expression vectors with cassettes that allow the rapid construction of assays for a large and diverse number of gene/reporter combinations. The development of such assays is shown to be straightforward, providing for a broad, flexible and biologically relevant platform for drug discovery.

    摘要翻译： 本发明提供用于药物发现的蛋白质片段互补测定法，特别是鉴定激活或抑制细胞途径的化合物。 基于与适当的PCA报道子组合的相互作用的蛋白质对的选择，测定可以以高通量或高含量模式进行，并且可以用于化合物文库的自动化筛选。 可以通过cDNA文库筛选来选择相互作用的对; 通过基因相互作用作图; 或通过路径的先验知识。 可以使用本文提供的方法构建荧光和发光测定。 针对多种报道者描述了适合于高通量或高含量（高上下文）测定形式的PCA报告人的选择，具体提供了单体酶和荧光蛋白的实例。 描述了用于构建生物化学途径中的一个或多个步骤的这种测定方法; 测试来自组合，天然产物，肽，抗体，核酸或其他不同文库的化合物对感兴趣的蛋白质或途径的影响; 并使用筛选结果来鉴定激活或抑制感兴趣的蛋白质或途径的特定化合物。 公开了单色和多色测定。 进一步公开的是具有盒的通用表达载体，其允许快速构建用于大量和多样化数量的基因/报道子组合的测定。 显示出这种测定的发展是直接的，为药物发现提供了广泛，灵活和生物相关的平台。

    Protein fragment complementation assays for high-throughput and high-content screening
    6.
    发明授权
    Protein fragment complementation assays for high-throughput and high-content screening 失效
    用于高通量和高含量筛选的蛋白质片段互补测定

    公开(公告)号：US07062219B2

    公开(公告)日：2006-06-13

    申请号：US10772021

    申请日：2004-02-05

    申请人： Stephen William Watson Michnick ,  Ingrid Remy ,  Marnie MacDonald ,  Jane Lamerdin ,  Helen Yu ,  John K. Westwick

    发明人： Stephen William Watson Michnick ,  Ingrid Remy ,  Marnie MacDonald ,  Jane Lamerdin ,  Helen Yu ,  John K. Westwick

    IPC分类号： C12Q1/00 ,  C07K14/00 ,  C12N15/11

    CPC分类号： G01N33/5011 ,  G01N33/5008 ,  G01N33/5041 ,  G01N33/542 ,  G01N33/6845 ,  G01N2500/02 ,  Y02A90/26

    摘要： The present invention provides protein single-color and multi-color protein fragment complementation assays for drug discovery, in particular to identify compounds that activate or inhibit cellular pathways. Based on the selection of an interacting protein pair combined with an appropriate PCA reporter such as monomeric enzymes and fluorescent proteins, the assays may be run in high-throughput or high-content mode and may be used in automated screening of libraries of compounds. Methods are described for constructing such assays for one or more steps in a biochemical pathway; testing the effects of compounds from combinatorial, natural product, peptide, antibody, nucleic acid or other diverse libraries on the protein or pathway(s) of interest; and using the results of the screening to identify specific compounds that activate or inhibit the protein or pathway(s) of interest. The development of such assays provides for a broad, flexible and biologically relevant platform for drug discovery.

    摘要翻译： 本发明提供用于药物发现的蛋白质单色和多色蛋白质片段互补测定法，特别是鉴定激活或抑制细胞途径的化合物。 基于与适当的PCA报告物如单体酶和荧光蛋白结合的相互作用的蛋白质对的选择，测定可以以高通量或高含量模式进行，并且可以用于化合物文库的自动筛选。 描述了用于构建生物化学途径中的一个或多个步骤的这种测定方法; 测试来自组合，天然产物，肽，抗体，核酸或其他不同文库的化合物对感兴趣的蛋白质或途径的影响; 并使用筛选结果来鉴定激活或抑制感兴趣的蛋白质或途径的特定化合物。 这种测定的开发提供了用于药物发现的广泛，灵活和生物相关的平台。

    Fragment complementation assays for G-protein-coupled receptors and their signaling pathways
    7.
    发明授权
    Fragment complementation assays for G-protein-coupled receptors and their signaling pathways 失效
    G蛋白偶联受体及其信号通路的片段互补测定

    公开(公告)号：US07488583B2

    公开(公告)日：2009-02-10

    申请号：US10947368

    申请日：2004-09-23

    申请人： John K. Westwick ,  Brigitte Keon ,  Marnie L. MacDonald

    发明人： John K. Westwick ,  Brigitte Keon ,  Marnie L. MacDonald

    IPC分类号： G01N33/566 ,  C07K14/705 ,  C07K19/00 ,  C12N15/62

    CPC分类号： G01N33/74 ,  C12Q1/00 ,  G01N33/5041 ,  G01N2333/726 ,  G01N2500/00

    摘要： The invention provides a method of screening a candidate drug, a compound library or a biological extract to identify activators or inhibitors of G-protein-coupled receptors or G-protein-coupled pathways, comprising: (A) using a fluorescent protein fragment complementation assay to construct an assay for one or more steps in a G-protein-coupled pathway; (B) testing the effects of the candidate drugs, compound library, or biological extract on the receptor or pathway of interest; and (C) using the results of the screening to identify specific agents that activate or inhibit the receptor or pathway of interest. The invention also provides a method for identifying a drug lead that modulates the activity of a G-protein-coupled pathway using a fluorescent protein fragment complementation assay. The method of the invention is used to identify agonists, antagonists, activators or inhibitors of G-protein coupled receptors or G-protein-coupled pathways.

    摘要翻译： 本发明提供了筛选候选药物，化合物文库或生物提取物以鉴定G蛋白偶联受体或G蛋白偶联途径的激活剂或抑制剂的方法，其包括：（A）使用荧光蛋白片段互补试验 构建G蛋白偶联途径中一个或多个步骤的测定法; （B）测试候选药物，化合物文库或生物提取物对感兴趣的受体或途径的影响; 和（C）使用筛选结果鉴定激活或抑制感兴趣的受体或途径的特异性试剂。 本发明还提供了用于鉴定使用荧光蛋白片段互补测定调节G蛋白偶联途径的活性的药物铅的方法。 本发明的方法用于鉴定G蛋白偶联受体或G蛋白偶联途径的激动剂，拮抗剂，激活剂或抑制剂。

    High-content and high throughput assays for identification of lipid-regulating pathways, and novel therapeutic agents for lipid disorders
    8.
    发明申请
    High-content and high throughput assays for identification of lipid-regulating pathways, and novel therapeutic agents for lipid disorders 审中-公开
    用于鉴定脂质调节途径的高含量和高通量测定，以及用于脂质疾病的新型治疗剂

    公开(公告)号：US20100081632A1

    公开(公告)日：2010-04-01

    申请号：US12382066

    申请日：2009-03-06

    申请人： Donna Oksenberg ,  Drew Sukovich ,  Tomoe Minami ,  Jane Lamerdin ,  John K. Westwick

    发明人： Donna Oksenberg ,  Drew Sukovich ,  Tomoe Minami ,  Jane Lamerdin ,  John K. Westwick

    IPC分类号： A61K31/69 ,  G01N33/53 ,  G01N33/573 ,  C40B30/04 ,  A61K31/35

    CPC分类号： G01N33/6845 ,  G01N33/542 ,  G01N33/92 ,  G01N2333/96411 ,  G01N2500/02

    摘要： A method of assaying protein-protein interactions associated with proteins involved in lipid pathways using a protein fragment complementation assays, said method comprising the steps of: (a) identifying protein molecules that interact with said protein associated with lipid pathways; (b) selecting a protein reporter molecule; (c) effecting fragmentation of said protein reporter molecule such that said fragmentation results in reversible loss of reporter function; (d) fusing or attaching fragments of said protein reporter molecule separately to said interacting protein molecules as defined in step (a); (e) transfecting cells with nucleic acid constructs coding for the products of step (d); (f) reassociating said reporter fragments through interactions of the protein molecules that are fused or attached to said fragments; and (g) measuring directly or Indirectly the activity of said reporter molecule resulting from the reassociation of said reporter fragments.

    摘要翻译： 一种使用蛋白质片段互补测定法测定涉及脂质途径的蛋白质相关的蛋白质 - 蛋白质相互作用的方法，所述方法包括以下步骤：（a）鉴定与所述与脂质途径相关的蛋白质相互作用的蛋白质分子; （b）选择蛋白质报告分子; （c）使所述蛋白质报告分子进行片段化，使得所述片段化导致报告基因功能的可逆损失; （d）将所述蛋白质报告分子的片段与步骤（a）中定义的所述相互作用蛋白分子分开融合或附着; （e）用编码步骤（d）的产物的核酸构建体转染细胞; （f）通过与所述片段融合或连接的蛋白质分子的相互作用使所述报道片段重新结合; 和（g）直接或间接测量所述报告分子的活性，所述活性由所述报道片段的重新连接而产生。

    JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers
    9.
    发明授权
    JNK inhibitors for use in combination therapy for treating or managing proliferative disorders and cancers 失效
    用于联合治疗用于治疗或控制增殖性疾病和癌症的JNK抑制剂

    公开(公告)号：US07351729B2

    公开(公告)日：2008-04-01

    申请号：US10384440

    申请日：2003-03-07

    申请人： Bernd M. Stein ,  John K. Westwick ,  Bruce W. Ennis

    发明人： Bernd M. Stein ,  John K. Westwick ,  Bruce W. Ennis

    IPC分类号： A61K31/41 ,  A61K31/47 ,  A61K31/44 ,  A61K31/535

    CPC分类号： A61K31/704 ,  A61K31/337 ,  A61K31/416 ,  A61K31/4196 ,  A61K31/454 ,  A61K31/4745 ,  A61K31/505 ,  A61K31/513 ,  A61K31/675 ,  A61K33/24 ,  A61K45/06 ,  A61K2300/00

    摘要： The present invention relates to methods and compositions designed for the treatment, management or prevention of cancer. The methods of the invention comprise the administration of an effective amount of one or more inhibitors of JNK in combination with the administration of an effective amount of one or more other agents useful for cancer therapy. The invention also provides pharmaceutical compositions comprising one or more inhibitors of JNK in combination with one or more other agents useful for cancer therapy. In particular, the invention is directed to methods of treatment and prevention of cancer by the administration of an effective amount of one or more inhibitors of JNK in combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies for treatment or prevention of cancer. Also included are methods of treatment of cancer by the administration of one or more inhibitors of JNK in combination with surgery, alone or in further combination with standard and experimental chemotherapies, hormonal therapies, bone marrow transplants, stem cell replacement therapies, biological therapies/immunotherapies and/or radiation therapies.

    摘要翻译： 本发明涉及设计用于治疗，管理或预防癌症的方法和组合物。 本发明的方法包括施用有效量的一种或多种JNK抑制剂与施用有效量的一种或多种其它可用于癌症治疗的试剂的组合。 本发明还提供包含一种或多种JNK抑制剂与一种或多种其它可用于癌症治疗的试剂组合的药物组合物。 特别地，本发明涉及通过给予有效量的一种或多种JNK抑制剂与标准和实验化学疗法，激素疗法，骨髓移植物，干细胞替代疗法，生物学方法，治疗和预防癌症的方法 用于治疗或预防癌症的治疗/免疫治疗和/或放射疗法。 还包括通过单独或与标准和实验化学疗法，激素治疗，骨髓移植，干细胞替代疗法，生物疗法/免疫疗法单独或进一步组合的一种或多种JNK抑制剂的给药来治疗癌症的方法 和/或放射疗法。