公开(公告)号：US20090036318A1

公开(公告)日：2009-02-05

申请号：US11831303

申请日：2007-07-31

申请人： Christina M. Grozinger ,  Christian A. Hassig ,  Stuart L. Schreiber

发明人： Christina M. Grozinger ,  Christian A. Hassig ,  Stuart L. Schreiber

IPC分类号： C40B30/00 ,  C07H21/04 ,  C12N15/63 ,  C12N5/10 ,  C12N9/00 ,  C07K16/40 ,  C12Q1/00

CPC分类号： C07H21/04 ,  A01K2217/05 ,  C12N9/16 ,  C12N9/78 ,  C12N9/80 ,  C12P21/00 ,  C12Q1/34 ,  G01N33/6875

摘要： The invention provides histone deacetylase class II nucleic acids and polypeptides, methods and reagents for their use, and related compounds including small molecule libraries containing class II histone deacetylase inhibitors.

摘要翻译： 本发明提供组蛋白脱乙酰酶II类核酸和多肽，其用途的方法和试剂，以及包含含有II类组蛋白脱乙酰酶抑制剂的小分子文库的相关化合物。

公开(公告)号：US07109377B2

公开(公告)日：2006-09-19

申请号：US10185364

申请日：2002-06-27

申请人： Stuart L. Schreiber ,  Matthew D. Shair ,  Derek S. Tan ,  Michael A. Foley ,  Brent R. Stockwell

发明人： Stuart L. Schreiber ,  Matthew D. Shair ,  Derek S. Tan ,  Michael A. Foley ,  Brent R. Stockwell

IPC分类号： C07C233/00

CPC分类号： C07D307/33 ,  B01J19/0046 ,  B01J2219/00317 ,  B01J2219/00364 ,  B01J2219/00367 ,  B01J2219/005 ,  B01J2219/00511 ,  B01J2219/00531 ,  B01J2219/00585 ,  B01J2219/00596 ,  B01J2219/00605 ,  B01J2219/0061 ,  B01J2219/00612 ,  B01J2219/0065 ,  B01J2219/00659 ,  B01J2219/00702 ,  C07C227/10 ,  C07C231/12 ,  C07C235/40 ,  C07C237/20 ,  C07C237/24 ,  C07C247/14 ,  C07C2601/14 ,  C07C2601/16 ,  C07D261/20 ,  C07D493/04 ,  C40B40/00 ,  C40B60/14 ,  C40B80/00 ,  G01N33/50 ,  Y10S435/975 ,  C07C229/34

摘要： The present invention provides complex compounds reminiscent of natural products and libraries thereof, as well as methods for their production. The inventive compounds and libraries of compounds are reminiscent of natural products in that they contain one or more stereocenters, and a high density and diversity of functionality. In general, the inventive libraries are synthesized from diversifiable scaffold structures, which are synthesized from readily available or easily synthesizable template structures. In certain embodiments, the inventive compounds and libraries are generated from diversifiable scaffolds synthesized from a shikimic acid based epoxyol template. In other embodiments, the inventive compounds and libraries are generated from diversifiable scaffolds synthesized from the pyridine-based template isonicotinamide. The present invention also provides a novel ortho-nitrobenzyl photolinker and a method for its synthesis. Furthermore, the present invention provides methods and kits for determining one or more biological activities of members of the inventive libraries. Additionally, the present invention provides pharmaceutical compositions containing one or more library members.

公开(公告)号：US06891021B2

公开(公告)日：2005-05-10

申请号：US10054712

申请日：2001-11-13

申请人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw

发明人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw

IPC分类号： A61K38/00 ,  A61K47/48 ,  C07D498/18 ,  C07F5/02 ,  C07H19/01 ,  C07K7/64 ,  C07K14/395 ,  C07K14/705 ,  C07K14/71 ,  C07K14/725 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C07K2/00 ,  C07K4/00

CPC分类号： C07D498/18 ,  A61K38/00 ,  A61K47/6425 ,  A61K48/00 ,  C07F5/025 ,  C07H19/01 ,  C07K7/645 ,  C07K14/395 ,  C07K14/705 ,  C07K14/7051 ,  C07K14/71 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/09 ,  C07K2319/20 ,  C07K2319/32 ,  C07K2319/42 ,  C07K2319/43 ,  C07K2319/60 ,  C07K2319/71 ,  C07K2319/715 ,  C07K2319/81 ,  C07K2319/90 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00

摘要： We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells

摘要翻译： 我们已经开发了细胞内蛋白质的调节（诱导型）二聚化或寡聚化的一般程序，并公开了使用该程序调节基因工程细胞中细胞特异性凋亡（程序性细胞死亡）的方法和材料

公开(公告)号：US20050095639A1

公开(公告)日：2005-05-05

申请号：US10998867

申请日：2004-11-29

申请人： Stuart L. Schreiber ,  Gavin MacBeath ,  Angela Koehler ,  Paul Hergenrother ,  Kristopher Depew

发明人： Stuart L. Schreiber ,  Gavin MacBeath ,  Angela Koehler ,  Paul Hergenrother ,  Kristopher Depew

IPC分类号： B01J19/00 ,  C07B61/00 ,  C07C311/49 ,  C40B30/04 ,  C40B40/04 ,  C40B50/14 ,  C40B60/14 ,  G01N33/543 ,  C12Q1/68 ,  G01N33/53

CPC分类号： G01N31/00 ,  B01J19/0046 ,  B01J2219/00387 ,  B01J2219/00454 ,  B01J2219/00459 ,  B01J2219/005 ,  B01J2219/00533 ,  B01J2219/00605 ,  B01J2219/0061 ,  B01J2219/00612 ,  B01J2219/00626 ,  B01J2219/00637 ,  B01J2219/0072 ,  C07B2200/11 ,  C07C311/49 ,  C40B30/04 ,  C40B40/04 ,  C40B50/14 ,  C40B60/14 ,  G01N33/54353 ,  Y10S436/809

摘要： The present invention provides compositions and methods to facilitate the identification of compounds that are capable of interacting with a biological macromolecule of interest. In one aspect, a composition is provided that comprises an array of one or more types of chemical compounds attached to a solid support, wherein the density of the array of compounds is at least 1000 spots per cm2. In particularly preferred embodiments, these compounds are attached to the solid support through a covalent interaction. In general, these inventive arrays are generated by: (1) providing a solid support, wherein said solid support is functionalized with a selected chemical moiety capable of interacting with a desired chemical compound to form an attachment; (2) providing one or more solutions of one or more types of compounds to be attached to the solid support; and (3) delivering said one or more types of compounds to the solid support, whereby an array is formed and the array of compounds has a density of at least 1000 spots per cm2. In another aspect, the present invention provides methods for utilizing these arrays to identify small molecule partners for biological macromolecules of interest comprising: (1) providing an array of compounds, wherein the array has a density of at least 1000 spots per cm2; (2) contacting the array with one of more types of biological macromolecules of interest; and (3) determining the interaction of specific small molecule-biological macromolecule partners.

摘要翻译： 本发明提供了有助于鉴定能够与感兴趣的生物大分子相互作用的化合物的组合物和方法。 在一个方面，提供了一种组合物，其包含连接到固体支持物上的一种或多种类型化学化合物的阵列，其中化合物阵列的密度为至少1000个点/ cm 2。 在特别优选的实施方案中，这些化合物通过共价相互作用连接到固体支持物上。 通常，这些本发明的阵列通过以下方式产生：（1）提供固体支持物，其中所述固体支持物用能够与所需化学化合物相互作用以形成附着物的选定化学部分官能化; （2）提供待连接到固体支持物上的一种或多种类型化合物的一种或多种溶液; 和（3）将所述一种或多种类型的化合物递送到固体支持物，由此形成阵列，并且化合物阵列具有至少1000个点/ cm 2的密度。 另一方面，本发明提供利用这些阵列鉴定感兴趣的生物大分子的小分子伴侣的方法，包括：（1）提供化合物阵列，其中阵列的密度至少为1000个点/ 2 ; （2）使阵列与感兴趣的多种生物大分子之一接触; 和（3）确定特定小分子 - 生物大分子伴侣的相互作用。

公开(公告)号：US06824987B1

公开(公告)日：2004-11-30

申请号：US09567910

申请日：2000-05-10

申请人： Stuart L. Schreiber ,  Gavin MacBeath ,  Angela N. Koehler ,  Paul Hergenrother ,  Kristopher M. Depew

发明人： Stuart L. Schreiber ,  Gavin MacBeath ,  Angela N. Koehler ,  Paul Hergenrother ,  Kristopher M. Depew

IPC分类号： G01N3353

CPC分类号： G01N31/00 ,  B01J19/0046 ,  B01J2219/00387 ,  B01J2219/00454 ,  B01J2219/00459 ,  B01J2219/005 ,  B01J2219/00533 ,  B01J2219/00605 ,  B01J2219/0061 ,  B01J2219/00612 ,  B01J2219/00626 ,  B01J2219/00637 ,  B01J2219/0072 ,  C07B2200/11 ,  C07C311/49 ,  C40B30/04 ,  C40B40/04 ,  C40B50/14 ,  C40B60/14 ,  G01N33/54353 ,  Y10S436/809

摘要： The present invention provides compositions and methods to facilitate the identification of compounds that are capable of interacting with a biological macromolecule of interest. In one aspect, a composition is provided that comprises an array of one or more types of chemical compounds attached to a solid support, wherein the density of the array of compounds is at least 1000 spots per cm2. In particularly preferred embodiments, these compounds are attached to the solid support through a covalent interaction. In general, these inventive arrays are generated by: (1) providing a solid support, wherein said solid support is functionalized with a selected chemical moiety capable of interacting with a desired chemical compound to form an attachment; (2) providing one or more solutions of one or more types of compounds to be attached to the solid support; and (3) delivering said one or more types of compounds to the solid support, whereby an array is formed and the array of compounds has a density of at least 1000 spots per cm2. In another aspect, the present invention provides methods for utilizing these arrays to identify small molecule partners for biological macromolecules of interest comprising: (1) providing an array of compounds, wherein the array has a density of at least 1000 spots per cm2; (2) contacting the array with one of more types of biological macromolecules of interest; and (3) determining the interaction of specific small molecule-biological macromolecule partners.

摘要翻译： 本发明提供了有助于鉴定能够与感兴趣的生物大分子相互作用的化合物的组合物和方法。 在一个方面，提供了包含连接到固体支持物上的一种或多种类型化学化合物的阵列的组合物，其中化合物阵列的密度为至少1000个斑点/ cm 2。 在特别优选的实施方案中，这些化合物通过共价相互作用连接到固体支持物上。 通常，这些本发明的阵列通过以下方式产生：（1）提供固体支持物，其中所述固体支持物用能够与所需化学化合物相互作用以形成附着物的选定化学部分官能化; （2）提供待连接到固体支持物上的一种或多种类型化合物的一种或多种溶液; 和（3）将所述一种或多种类型的化合物递送到固体支持物，由此形成阵列，并且所述化合物阵列的密度至少为1000个点/ cm 2。 另一方面，本发明提供了利用这些阵列来识别感兴趣的生物大分子的小分子配偶体的方法，包括：（1）提供化合物阵列，其中阵列的密度至少为1000个点/ cm 2 ; （2）使阵列与感兴趣的多种生物大分子之一接触; 和（3）确定特定小分子 - 生物大分子伴侣的相互作用。

公开(公告)号：US6043082A

公开(公告)日：2000-03-28

申请号：US157753

申请日：1998-09-16

申请人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Steffan N. Ho ,  Peter Belshaw

发明人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Steffan N. Ho ,  Peter Belshaw

IPC分类号： A61K38/00 ,  A61K47/48 ,  A61K48/00 ,  C07D498/18 ,  C07F5/02 ,  C07H19/01 ,  C07K7/64 ,  C07K14/395 ,  C07K14/705 ,  C07K14/71 ,  C07K14/715 ,  C07K14/725 ,  C12N15/12 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P17/18 ,  C12N15/85

CPC分类号： C07D498/18 ,  A61K47/48276 ,  A61K48/00 ,  C07F5/025 ,  C07H19/01 ,  C07K14/395 ,  C07K14/705 ,  C07K14/7051 ,  C07K14/71 ,  C07K14/715 ,  C07K7/645 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P17/188 ,  A01K2217/05 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/09 ,  C07K2319/20 ,  C07K2319/32 ,  C07K2319/42 ,  C07K2319/43 ,  C07K2319/60 ,  C07K2319/71 ,  C07K2319/715 ,  C07K2319/81 ,  C07K2319/90

摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).

公开(公告)号：US5871753A

公开(公告)日：1999-02-16

申请号：US473985

申请日：1995-06-07

申请人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw ,  Steffan Ho

发明人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw ,  Steffan Ho

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K47/48 ,  C07D498/18 ,  C07F5/02 ,  C07H19/01 ,  C07K7/64 ,  C07K14/395 ,  C07K14/71 ,  C07K14/725 ,  C12N1/19 ,  C12N5/10 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P21/00 ,  C12R1/85 ,  C12R1/91 ,  A61K45/00 ,  A61K38/13 ,  C07D491/06 ,  C07K5/12

CPC分类号： C07D498/18 ,  A61K47/48276 ,  C07F5/025 ,  C07H19/01 ,  C07K14/395 ,  C07K14/7051 ,  C07K14/71 ,  C07K7/645 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/09 ,  C07K2319/20 ,  C07K2319/32 ,  C07K2319/42 ,  C07K2319/43 ,  C07K2319/60 ,  C07K2319/71 ,  C07K2319/715 ,  C07K2319/81 ,  C07K2319/90

摘要： Methods and compositions are provided for modified cells, where a chimeric protein consisting of a ligand binding domain fused to an action domain is employed which initiates a signal which activates a biological process: transcription of at least one gene, usually a second construct introduced into the host cells; exocytosis; or an extracellular process. The second construct optimally present provides for a promoter which responds to a transcriptional activation action domain to provide for transcription, when an appropriate ligand binds to the ligand binding domain. Exemplary of the system is the use of an FKBP/CD3.zeta. or transcription factor fusion protein, using dimeric FK506 or FK520 as the ligand and a promoter responsive to NF-AT or other transcription factor requiring two molecules for transcriptional activation.

摘要翻译： 为修饰的细胞提供方法和组合物，其中使用由与活性结构域融合的配体结合结构域组成的嵌合蛋白，其启动激活生物学过程的信号：至少一种基因的转录，通常是引入 宿主细胞; 胞吐作用 或细胞外过程。 当适当的配体结合配体结合结构域时，最佳存在的第二种构建体提供响应于转录激活作用结构域以提供转录的启动子。 该系统的示例是使用二聚体FK506或FK520作为配体的FKBP / CD3ζ或转录因子融合蛋白，以及对NF-AT或需要两个分子进行转录激活的其他转录因子的启动子。

公开(公告)号：US5869337A

公开(公告)日：1999-02-09

申请号：US388653

申请日：1995-02-14

申请人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw

发明人： Gerald R. Crabtree ,  Stuart L. Schreiber ,  David M. Spencer ,  Thomas J. Wandless ,  Peter Belshaw

IPC分类号： A61K38/00 ,  A61K47/48 ,  A61K48/00 ,  C07D498/18 ,  C07F5/02 ,  C07H19/01 ,  C07K7/64 ,  C07K14/395 ,  C07K14/705 ,  C07K14/71 ,  C07K14/715 ,  C07K14/725 ,  C12N15/12 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P17/18 ,  C12N5/10 ,  C12N5/08 ,  C12N15/79

CPC分类号： C07D498/18 ,  A61K47/48276 ,  A61K48/00 ,  C07F5/025 ,  C07H19/01 ,  C07K14/395 ,  C07K14/705 ,  C07K14/7051 ,  C07K14/71 ,  C07K14/715 ,  C07K7/645 ,  C12N15/62 ,  C12N15/63 ,  C12P15/00 ,  C12P17/188 ,  A01K2217/05 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/03 ,  C07K2319/035 ,  C07K2319/09 ,  C07K2319/20 ,  C07K2319/32 ,  C07K2319/42 ,  C07K2319/43 ,  C07K2319/60 ,  C07K2319/71 ,  C07K2319/715 ,  C07K2319/81 ,  C07K2319/90

摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy.

公开(公告)号：US4322537A

公开(公告)日：1982-03-30

申请号：US155059

申请日：1980-06-02

申请人： Stuart L. Schreiber

发明人： Stuart L. Schreiber

IPC分类号： C07D211/70 ,  C07D213/54 ,  C07C97/03

CPC分类号： C07D211/70

摘要： Tertiary amines in which at least one group bonded directly to the nitrogen atom is alkyl of 2 to 20 carbon atoms or in which two or more groups bonded directly to the nitrogen atom together are alkylene of 4 to 7 carbon atoms, are oxidized by trihaloacetyl anhydride or trihaloacetyl halide to mono- and di-trihaloacetylated alpha, beta-enamines.

摘要翻译： 其中至少一个直接与氮原子键合的基团为碳原子数为2〜20的烷基或其中两个或更多个直接与氮原子一起键合的基团一起为4至7个碳原子的亚烷基的叔胺被三卤代乙酸酐氧化 或三卤代乙酰卤与单 - 和二 - 三卤乙酰化的α，β-烯胺。