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。

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。

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。

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。

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。

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。

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。

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。

公开(公告)号：US08994352B2

公开(公告)日：2015-03-31

申请号：US13364711

申请日：2012-02-02

申请人： Jack Zhu ,  Basa Wang ,  Kevin Yao ,  Helen Yu

发明人： Jack Zhu ,  Basa Wang ,  Kevin Yao ,  Helen Yu

IPC分类号： H02M3/156 ,  H02M1/00

CPC分类号： H02M3/156 ,  H02M2001/0032 ,  Y02B70/16

摘要： A switching regulator and control method for the same. The switching regulator employs a hybrid mode. A ramp voltage signal is added to the current sense signal to make the ramp voltage signal overtake the current information when the duty cycle becomes low.

摘要翻译： 一种开关调节器及其控制方法。 开关稳压器采用混合模式。 当电流检测信号加上斜坡电压信号时，当占空比变低时，使斜坡电压信号超过电流信息。

公开(公告)号：US20130043856A1

公开(公告)日：2013-02-21

申请号：US13343615

申请日：2012-01-04

申请人： Basa Wang ,  Kevin Yao ,  Jack Zhu ,  Helen Yu

发明人： Basa Wang ,  Kevin Yao ,  Jack Zhu ,  Helen Yu

IPC分类号： G05F1/10

CPC分类号： H02M3/156 ,  H02M2001/0025

摘要： The present invention relates to a circuit and method of generating a ramp compensation voltage as might be used in a switching regulator. The ramp compensation voltage comprises: a charging current generating circuit configured to receive a switching signal having a frequency of fs, a duty cycle of D and a period of Ts, the charging current generating circuit generating a charging current in direct proportion to f s ( 1 - D )  DTs ; and a voltage generating circuit for generating a quadratic ramp compensation voltage by means of the charging current. The resulting ramp compensation voltage enables the switching regulator to operate over a broad range of duty cycles. The generated ramp compensation voltage has an amplitude as low as possible, the generated compensation slope approximates to the target compensation slope as close as possible, and over compensation at low duty cycles is reduced as far as possible.

摘要翻译： 本发明涉及一种产生可能用于开关调节器中的斜坡补偿电压的电路和方法。 斜坡补偿电压包括：充电电流产生电路，被配置为接收具有频率fs，占空比D和周期Ts的开关信号，充电电流产生电路产生与fs（1）成正比的充电电流 - D）DT 以及用于通过充电电流产生二次斜坡补偿电压的电压产生电路。 所产生的斜坡补偿电压使开关稳压器能够在宽范围的占空比下工作。 产生的斜坡补偿电压的幅度尽可能的低，产生的补偿斜率尽可能接近目标补偿斜率，尽可能地减少低占空比的过补偿。