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1. 发明申请

US20050181452A1 Fragment complementation assays for G-protein-coupled receptors and their signaling pathways 失效
标题翻译： 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：US20050181452A1
公开(公告)日：2005-08-18
申请号：US10947368
申请日：2004-09-23
申请人： John Westwick , Brigitte Keon , Marnie MacDonald
发明人： John Westwick , Brigitte Keon , Marnie MacDonald
IPC分类号： C07K16/28 , C12P21/02 , C12Q1/00 , C12Q1/68 , G01N20060101 , G01N33/50 , G01N33/53 , G01N33/543 , G01N33/74
CPC分类号： G01N33/74 , C12Q1/00 , G01N33/5041 , G01N2333/726 , G01N2500/00
摘要： This invention relates generally to the fields of biology, molecular biology, chemistry and biochemistry. The invention is directed to a large number of novel assays for G-protein-coupled receptors (GPCRs) and their signaling pathways. Methods are described for constructing such assays for one or more steps in a GPCR pathway. The invention can be used for functional characterization of GPCRs, target validation, de-orphanization of receptors, high-throughput screening, high-content screening, pharmacological profiling, and other drug discovery applications. The assays can be used directly to assess whether a compound library or a biological extract contains an agonist or antagonist of a receptor. Assay compositions are also provided. The development of such assays is shown to be straightforward, providing for a broad, flexible and biologically relevant platform for the discovery of novel drugs and natural ligands that act on GPCRs or their cognate pathways.
摘要翻译：本发明一般涉及生物学，分子生物学，化学和生物化学领域。本发明涉及大量用于G蛋白偶联受体（GPCR）的新型测定及其信号通路。描述了用于构建GPCR途径中一个或多个步骤的这种测定法的方法。本发明可用于GPCR的功能表征，目标验证，受体去孤儿化，高通量筛选，高含量筛选，药理学分析和其他药物发现应用。所述测定可直接用于评价化合物文库或生物提取物是否含有受体的激动剂或拮抗剂。还提供了测定组合物。显示出这种测定的发展是直接的，为广泛，灵活和生物学上相关的平台发现用于GPCR或其同源途径的新型药物和天然配体的发现。

2. 发明申请

US20080064040A1 Monitoring gene silencing and annotating gene function in living cells 审中-公开
标题翻译：监测基因沉默和注释活细胞中的基因功能
公开(公告)号：US20080064040A1
公开(公告)日：2008-03-13
申请号：US11819769
申请日：2007-06-29
申请人： Stephen Watson Michnick , Barbara Belisle , Marnie MacDonald , John Westwick , Jane Lamerdin
发明人： Stephen Watson Michnick , Barbara Belisle , Marnie MacDonald , John Westwick , Jane Lamerdin
IPC分类号： C12Q1/68 , G01N33/50
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, and to determine if a non-targeted gene participates in a pathway of interest or is functionally linked to another gene or protein. The combination of annotation reagents with such cell-based assays is useful for mapping genes (proteins) into cellular pathways on a genome-wide scale. 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, to determine the level of gene silencing that is achieved, 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的敏感性和特异性，并确定非靶向基因是否参与感兴趣的途径或与另一种功能相关基因或蛋白质。注释试剂与这种基于细胞的测定法的组合可用于将基因（蛋白质）在基因组范围内映射到细胞途径中。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，确定实现的基因沉默水平，并将新基因映射到生物化学途径中，并鉴定新的药物靶标。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。

3. 发明申请

US20070212677A1 Identifying off-target effects and hidden phenotypes of drugs in human cells 审中-公开
标题翻译：识别药物在人类细胞中的脱靶效应和隐性表型
公开(公告)号：US20070212677A1
公开(公告)日：2007-09-13
申请号：US11513068
申请日：2006-08-31
申请人： Marnie MacDonald , Jane Lamerdin , Stephen Owens , Brigitte Keon , Graham Bilter , Zhidi Shang , Zhengping Huang , Helen Yu , Jennifer Dias , Tomoe Minami , Stephen Michnick , John Westwick
发明人： Marnie MacDonald , Jane Lamerdin , Stephen Owens , Brigitte Keon , Graham Bilter , Zhidi Shang , Zhengping Huang , Helen Yu , Jennifer Dias , Tomoe Minami , Stephen Michnick , John Westwick
IPC分类号： C12Q1/00 , C12Q1/68 , G01N33/53 , G06F19/00
CPC分类号： G01N33/5008
摘要： This invention provides principles, methods and compositions for ascertaining the mechanism of action of pharmacologically important compounds in the context of network biology, across the entire scope of the complex pathways of living cells. Importantly, the principles, methods and compositions provided allow a rapid assessment of the on-pathway and off-pathway effects of lead compounds and drug candidates in living cells, and comparisons of lead compounds with well-characterized drugs and toxicants to identify patterns associated with efficacy and toxicity. The invention will be useful in improving the drug discovery process, in particular by identifying drug leads with desired safety and efficacy and in effecting early attrition of compounds with potential adverse effects in man.
摘要翻译：本发明提供了在网络生物学背景下确定药物重要化合物在活细胞复合途径的整个范围内的作用机制的原理，方法和组合物。重要的是，提供的原理，方法和组合可以快速评估铅化合物和药物候选物在活细胞中的通路和脱离途径作用，以及铅化合物与良好表征的药物和毒物的比较，以鉴定与功效和毒性。本发明将有助于改进药物发现过程，特别是通过鉴定具有期望的安全性和功效的药物引线并且实现对人具有潜在不利影响的化合物的早期损耗。

4. 发明申请

US20060224331A1 Protein fragment complementation assays for high-throughput and high-content screening 失效
标题翻译：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：US20060224331A1
公开(公告)日：2006-10-05
申请号：US11450379
申请日：2006-06-12
申请人： Stephen Watson Michnick , Ingrid Remy , Marnie MacDonald , Jane Lamerdin , Helen Yu , John Westwick
发明人： Stephen Watson Michnick , Ingrid Remy , Marnie MacDonald , Jane Lamerdin , Helen Yu , John Westwick
IPC分类号： C40B30/02 , G06F19/00
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，灵活和生物相关的平台。

5. 发明申请

US20060160109A1 Harnessing network biology to improve drug discovery 审中-公开
标题翻译：利用网络生物学改善药物发现
公开(公告)号：US20060160109A1
公开(公告)日：2006-07-20
申请号：US11282745
申请日：2005-11-21
申请人： Marnie MacDonald , John Westwick , Brigitte Keon , Jane Lamerdin , Stephen Michnick
发明人： Marnie MacDonald , John Westwick , Brigitte Keon , Jane Lamerdin , Stephen Michnick
IPC分类号： C40B40/08 , C40B40/10
CPC分类号： G01N33/5008 , B82Y10/00 , B82Y30/00 , C12Q1/025 , G01N33/5014 , G01N33/5041
摘要： This invention provides principles, methods and compositions for ascertaining the mechanism of action of pharmacologically important compounds in the context of network biology, across the entire scope of the complex pathways of living cells. Importantly, the principles, methods and compositions provided allow a rapid assessment of the on-pathway and off-pathway effects of lead compounds and drug candidates in living cells, and comparisons of lead compounds with well-characterized drugs and toxicants to identify patterns associated with efficacy and toxicity. The invention will be useful in improving the drug discovery process, in particular by identifying drug leads with desired safety and efficacy and in effecting early attrition of compounds with potential adverse effects in man.
摘要翻译：本发明提供了在网络生物学背景下确定药物重要化合物在活细胞复合途径的整个范围内的作用机制的原理，方法和组合物。重要的是，提供的原理，方法和组合可以快速评估铅化合物和药物候选物在活细胞中的通路和脱离途径作用，以及铅化合物与良好表征的药物和毒物的比较，以鉴定与功效和毒性。本发明将有助于改进药物发现过程，特别是通过鉴定具有期望的安全性和功效的药物引线并且实现具有潜在副作用的化合物的早期损耗。

6. 发明申请

US20060094682A1 Kinase inhibitors for the treatment of diabetes and obesity 审中-公开
标题翻译：用于治疗糖尿病和肥胖症的激酶抑制剂
公开(公告)号：US20060094682A1
公开(公告)日：2006-05-04
申请号：US11260164
申请日：2005-10-28
申请人： John Westwick , Jane Lamerdin , Stephen Owens , Marnie MacDonald
发明人： John Westwick , Jane Lamerdin , Stephen Owens , Marnie MacDonald
IPC分类号： A61K48/00 , A61K38/54 , A61K39/395
CPC分类号： C12Q1/485 , G01N33/502 , G01N33/6893 , G01N2500/00
摘要： The present invention discloses a method of treating an individual or animal with diabetes and/or obesity. The method comprises administering to the individual or animal a therapeutically effective amount of a protein tyrosine kinase inhibitor. Preferably, the preventative and therapeutic methods of the present invention involve administering—to a mammal in need thereof—a therapeutically effective amount of an inhibitor of a c-Src-family protein tyrosine kinase. The invention pertains to pharmaceutical compositions containing an inhibitor of a c-Src-family protein tyrosine kinase or an analog or metabolite thereof, or an inhibitor of another protein tyrosine kinase, and a pharmaceutically acceptable carrier. Purines and pyrimidines and other molecules useful in the treatment of diabetes and obesity are provided herein, in particular, pyrazolopyrimidines, cyanoquinolines, phenylaminopyrimidines, anilinoquinazolines and related compounds. The invention also provides cellular targets and assay compositions useful for the identification of additional novel therapeutic agents for the treatment of these disorders.
摘要翻译：本发明公开了一种用糖尿病和/或肥胖症治疗个体或动物的方法。该方法包括向个体或动物施用治疗有效量的蛋白酪氨酸激酶抑制剂。优选地，本发明的预防和治疗方法包括向有需要的哺乳动物施用治疗有效量的c-Src家族蛋白酪氨酸激酶的抑制剂。本发明涉及含有c-Src家族蛋白酪氨酸激酶或其类似物或代谢物的抑制剂或其它蛋白酪氨酸激酶的抑制剂和药学上可接受的载体的药物组合物。本文提供了可用于治疗糖尿病和肥胖症的嘌呤和嘧啶和其它分子，特别是吡唑并嘧啶，氰基喹啉，苯基氨基嘧啶，苯胺基喹唑啉和相关化合物。本发明还提供用于鉴定用于治疗这些疾病的其它新型治疗剂的细胞靶和测定组合物。

7. 发明申请

US20050221280A1 Protein-protein interactions for pharmacological profiling 审中-公开
标题翻译：蛋白质 - 蛋白质相互作用进行药理学分析
公开(公告)号：US20050221280A1
公开(公告)日：2005-10-06
申请号：US11101397
申请日：2005-04-08
申请人： John Westwick , Brigitte Keon , Marnie MacDonald , Stephen William Michnick
发明人： John Westwick , Brigitte Keon , Marnie MacDonald , Stephen William Michnick
IPC分类号： C12Q1/00 , C40B30/04 , G01N33/50 , G01N33/68 , G06F19/12
CPC分类号： C40B30/04 , G01N33/5008 , G01N33/5014 , G01N33/502 , G01N33/5041 , G01N33/68 , G01N33/6845 , G16B5/00 , Y02A90/26
摘要： The present invention provides methods for performing pharmacological profiling of a chemical compound, in particular to improve drug safety and efficacy at an early stage in the drug development process. The chemical compound may be a test compound, drug lead, known drug or toxicant. The compound is profiled against a panel of assays. Preferred embodiments of the invention include high-content assays for protein-protein interactions. The compositions and methods of the invention can be used to identify pathways underlying drug efficacy, safety, and toxicity; and to effect attrition of novel compounds with undesirable or toxic properties. The compositions and methods of the invention can also be used to identify new uses of therapeutic agents, to screen libraries of chemical compounds, to perform lead optimization, and to perform studies of structure-activity relationships in the context of intact cells. The compositions and methods of the invention can be applied to any test compound, drug, drug target, pathway, and therapeutic indication.
摘要翻译：本发明提供了用于进行化学化合物的药理学分析的方法，特别是在药物开发过程的早期阶段提高药物安全性和功效。化合物可以是试验化合物，药物铅，已知药物或毒物。该化合物与一组测定法比较。本发明的优选实施方案包括用于蛋白质 - 蛋白质相互作用的高含量测定。本发明的组合物和方法可用于鉴定潜在药物功效，安全性和毒性的途径; 并且具有不希望的或毒性的新型化合物的磨损。本发明的组合物和方法还可以用于鉴定治疗剂的新用途，筛选化学化合物的文库，进行铅优化，以及在完整细胞的上下文中进行结构 - 活性关系的研究。本发明的组合物和方法可以应用于任何试验化合物，药物，药物靶标，途径和治疗适应症。

8. 发明申请

US20060094059A1 Methods for identifying new drug leads and new therapeutic uses for known drugs 审中-公开
标题翻译：识别新药物的方法和已知药物的新治疗用途
公开(公告)号：US20060094059A1
公开(公告)日：2006-05-04
申请号：US11230569
申请日：2005-09-21
申请人： John Westwick , Marnie MacDonald , Helen Yu , Stephen Owens , Stephen Michnick
发明人： John Westwick , Marnie MacDonald , Helen Yu , Stephen Owens , Stephen Michnick
IPC分类号： C40B40/10 , G01N33/53
CPC分类号： G01N33/5005 , G01N33/5035 , G01N33/5041
摘要： The screening system utilizes dynamic measurements of pathway activity to detect the activities of drugs within cellular pathways. The methods of the invention can be used to identify previously unknown drug activities and therapeutic uses, even for drugs that have been well characterized with standard biochemical assays. We demonstrated the utility of the invention by screening a portion of the known pharmacopeia. We identified dozens of drugs, previously or currently marked for a variety of indications, with surprising and previously-unsuspected activity against ‘hallmark’ cancer pathways. We also showed that over 20 of these drugs indeed have anti-proliferative activity in human tumor cells, underscoring the utility and predictability of the screening system. The methodology will extend the utility of the current pharmacopeia and provide the basis for de novo discovery of drugs with a broad range of therapeutic indications.
摘要翻译：筛选系统利用通路活性的动态测量来检测细胞通路内药物的活性。本发明的方法可以用于鉴定以前未知的药物活性和治疗用途，即使对于通过标准生化测定法进行了充分表征的药物也是如此。我们通过筛选一部分已知药典证明了本发明的效用。我们确定了以前或目前标有各种适应症的数十种药物，对“标志”癌症途径感到惊奇和先前不知情的活动。我们还显示，超过20种这些药物确实在人类肿瘤细胞中具有抗增殖活性，强调了筛选系统的效用和可预测性。该方法将扩大目前药典的效用，为从头发现具有广泛治疗适应症的药物提供依据。

9. 发明申请

US20060040338A1 Pharmacological profiling of drugs with cell-based assays 审中-公开
标题翻译：用基于细胞的测定法对药物进行药理学分析
公开(公告)号：US20060040338A1
公开(公告)日：2006-02-23
申请号：US11205021
申请日：2005-08-17
申请人： John Westwick , Helen Yu , Marnie MacDonald
发明人： John Westwick , Helen Yu , Marnie MacDonald
IPC分类号： C12Q1/02 , C12M1/34
CPC分类号： C12Q1/025 , G01N33/5023 , G01N33/5035 , G01N33/5041 , G01N33/5097 , G01N2440/00 , G01N2440/10 , G01N2440/12 , G01N2440/36 , G01N2440/38 , G01N2500/10
摘要： The instant invention provides a method for establishing safety profiles for chemical compounds, as well as pharmacological profiling said method comprising (A) testing the effects of said chemical compounds on the amount and/or post-translational modifications of two or more macromolecules in intact cells; (B) constructing a pharmacological profile based on the results of said tests; and (C) comparing said profile to the profile(s) of drugs with established safety characteristics. Additionally, the invention is also directed to a composition comprising an assay panel, said panel comprising at least one high-content assay for the amount and/or post-translational modification of a protein and at least one high-content assay for the amount and/or subcellular location of a protein-protein interaction.
摘要翻译：本发明提供了一种用于建立化学化合物安全性的方法，以及药理学分析，所述方法包括（A）测试所述化合物对完整细胞中两种或更多种大分子的量和/或翻译后修饰的影响 ; （B）基于所述测试的结果构建药理学特征; 和（C）将所述外形与具有确定的安全特性的药物的特征进行比较。此外，本发明还涉及包含测定面板的组合物，所述面板包含至少一种用于蛋白质的量和/或翻译后修饰的高含量测定法，以及至少一种高含量测定法，其量和/ /或蛋白质 - 蛋白质相互作用的亚细胞位置。

10. 发明申请

US20060009506A1 Drugs for the treatment of neoplastic disorders 审中-公开
标题翻译：用于治疗肿瘤性疾病的药物
公开(公告)号：US20060009506A1
公开(公告)日：2006-01-12
申请号：US11174630
申请日：2005-07-06
申请人： John Westwick , Helen Yu , Stephen Owens , Marnie MacDonald
发明人： John Westwick , Helen Yu , Stephen Owens , Marnie MacDonald
IPC分类号： A61K31/4172
CPC分类号： A61K31/4172
摘要： The invention features a method for treating a patient having a cancer or other neoplasm, by administering to the patient one of the following drugs or a metabolite or analog thereof: cinnarizine; desipramine; fenofibrate; flunarizine; isoreserpine; nicardipine; promazine; promethazine; suloctidil; terfenadine; atorvastatin; mebeverine; sertraline; albendazole; bepridil; bergaptene; clomiphene; dichlorophene; droperidol; mebendazole; meclocycline; metergoline; ramiphenazone; sanguinarine; dipyrone; nicardipine; or 4-dimethylaminoantipyrine.
摘要翻译：本发明的特征在于通过向患者施用以下药物之一或其代谢物或类似物来治疗患有癌症或其它肿瘤的患者的方法：cinnarizine; 地昔帕明非诺贝特氟桂利嗪异硬脂尼卡地平吩嗪异丙嗪 suloctidil; 特非那定阿托伐他汀 mebeverine; 舍曲林阿苯达唑贝普利伯格林克罗米酚二氯酚氟哌利多甲苯咪唑麦环加甲麦角林雷米芬他血缘关系二吡喃酮尼卡地平或4-二甲基氨基安替比林。

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