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1. 发明申请

US20060035325A1 Regulated apoptosis 审中-公开
公开(公告)号：US20060035325A1
公开(公告)日：2006-02-16
申请号：US11038326
申请日：2005-01-18
申请人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Peter Belshaw
发明人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Peter Belshaw
IPC分类号： C07K14/715 , C07H21/04 , C12P21/06 , C12N15/86
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.

2. 发明申请

US20050209265A1 Modulating a pharmacokinetic property of a drug by administering a bifunctional molecule containing the drug 有权
标题翻译：通过施用含有该药物的双官能分子来调节药物的药代动力学性质
公开(公告)号：US20050209265A1
公开(公告)日：2005-09-22
申请号：US11011776
申请日：2004-12-13
申请人： Roger Briesewitz , Gerald Crabtree , Thomas Wandless
发明人： Roger Briesewitz , Gerald Crabtree , Thomas Wandless
IPC分类号： A61K47/48 , A61K31/4745
CPC分类号： A61K47/55 , A61K47/54 , Y10S530/812
摘要： Bifunctional molecules and methods for their use are provided. The subject bifunctional molecules are conjugates of a drug moiety and a pharmacokinetic modulating moiety, where these two moieties are optionally joined by a linking group. The bifunctional molecules are further characterized in that they exhibit at least one modulated pharmacokinetic property upon administration to a host as compared to a free drug control. The subject bifunctional molecules find use in a variety of therapeutic applications.
摘要翻译：提供了双功能分子及其使用方法。主题双功能分子是药物部分和药代动力学调节部分的缀合物，其中这两个部分任选地通过连接基团连接。双官能分子的特征还在于，与游离药物对照相比，它们在施用于宿主时表现出至少一种调节的药代动力学性质。主题双功能分子可用于各种治疗应用。

3. 发明申请

US20050209146A1 Administering bifunctional molecules containing a drug moiety and presenter protein ligand for therapy 有权
标题翻译：管理含有药物部分的双功能分子和用于治疗的展示蛋白配体
公开(公告)号：US20050209146A1
公开(公告)日：2005-09-22
申请号：US11011499
申请日：2004-12-13
申请人： Roger Briesewitz , Gerald Crabtree , Thomas Wandless , Gregory Ray , Kurt Vogel
发明人： Roger Briesewitz , Gerald Crabtree , Thomas Wandless , Gregory Ray , Kurt Vogel
IPC分类号： A61K38/00 , A61K38/17 , A61K47/48 , C07K5/10 , C07K7/06 , C12N9/90
CPC分类号： C12N9/90 , A61K38/00 , A61K47/54 , A61K47/552 , C07K5/1027 , C07K7/06 , C07K2319/00 , Y10S530/812
摘要： Bifunctional molecules and methods for their use in the production of binary complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. In the subject methods, an effective amount of the bifunctional molecule is administered to the host. The bifunctional molecule binds to the presenter protein to produce a binary complex that exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The subject methods and compositions find use in a variety of therapeutic applications.
摘要翻译：提供了双功能分子及其在宿主生产二元配合物中的应用。双功能分子是药物部分和呈递蛋白质配体的缀合物。在本方法中，向宿主施用有效量的双功能分子。与相应的游离药物相比，双功能分子与展示蛋白结合以产生显示出改善的亲和力，特异性或选择性中的至少一种的二元复合物。主题方法和组合物可用于各种治疗应用。

4. 发明申请

US20100323420A1 REGULATED APOPTOSIS 失效
标题翻译：调节性病变
公开(公告)号：US20100323420A1
公开(公告)日：2010-12-23
申请号：US12684064
申请日：2010-01-07
申请人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Peter Belshaw
发明人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Peter Belshaw
IPC分类号： C12N9/90 , C12N15/63 , C12N5/10 , C12N9/96
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，并且公开了使用该方法在基因工程细胞中调节启动细胞特异性凋亡（程序性细胞死亡）的方法和材料。

5. 发明授权

US07390784B2 Administering bifunctional molecules containing a drug moiety and presenter protein ligand for therapy 有权
标题翻译：管理含有药物部分的双功能分子和用于治疗的展示蛋白配体
公开(公告)号：US07390784B2
公开(公告)日：2008-06-24
申请号：US11011499
申请日：2004-12-13
申请人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt W. Vogel
发明人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt W. Vogel
IPC分类号： A61K38/00 , A61K38/52 , C12N11/02 , C07K1/00 , C07K17/02
CPC分类号： C12N9/90 , A61K38/00 , A61K47/54 , A61K47/552 , C07K5/1027 , C07K7/06 , C07K2319/00 , Y10S530/812
摘要： Bifunctional molecules and methods for their use in the production of binary complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. In the subject methods, an effective amount of the bifunctional molecule is administered to the host. The bifunctional molecule binds to the presenter protein to produce a binary complex that exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The subject methods and compositions find use in a variety of therapeutic applications.
摘要翻译：提供了双功能分子及其在宿主生产二元配合物中的应用。双功能分子是药物部分和展示蛋白质配体的缀合物。在本方法中，向宿主施用有效量的双功能分子。与相应的游离药物相比，双功能分子与展示蛋白结合以产生显示出改善的亲和力，特异性或选择性中的至少一种的二元复合物。主题方法和组合物可用于各种治疗应用。

6. 发明授权

US06316418B1 Regulated apoptosis 失效
标题翻译：调节凋亡
公开(公告)号：US06316418B1
公开(公告)日：2001-11-13
申请号：US09302629
申请日：1999-04-30
申请人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Peter Belshaw , Steffan N Ho
发明人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Peter Belshaw , Steffan N Ho
IPC分类号： A61K3170
CPC分类号： C07D498/18 , A01K2217/05 , A61K38/00 , A61K47/6425 , A61K48/00 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , 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 , C12P17/188
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，并且公开了使用该方法在基因工程细胞中调节启动细胞特异性凋亡（程序性细胞死亡）的方法和材料。

7. 发明申请

US20060078969A1 Regulated transcription of targeted genes and other biological events 审中-公开
公开(公告)号：US20060078969A1
公开(公告)日：2006-04-13
申请号：US11175021
申请日：2005-07-05
申请人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Steffan Ho , Peter Belshaw
发明人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Steffan Ho , Peter Belshaw
IPC分类号： C07K14/705 , C07H21/04 , C12P21/04
CPC分类号： C07K14/705 , A61K38/00 , A61K47/6425 , C07D498/18 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , 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 , C12N15/1055 , C12N15/62 , C12N15/63 , C12N15/67 , C12P15/00
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 ζ 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 “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).

8. 发明授权

US06921531B2 Administering bifunctional molecules containing a drug moiety and presenter protein ligand for therapy 有权
标题翻译：管理含有药物部分的双功能分子和用于治疗的展示蛋白配体
公开(公告)号：US06921531B2
公开(公告)日：2005-07-26
申请号：US10025936
申请日：2001-12-21
申请人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt William Vogel
发明人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt William Vogel
IPC分类号： A61K38/00 , A61K38/17 , A61K47/48 , C07K5/10 , C07K7/06 , C12N9/90 , A61K38/52 , C07K1/00 , C07K17/02 , C12N11/02
CPC分类号： C12N9/90 , A61K38/00 , A61K47/54 , A61K47/552 , C07K5/1027 , C07K7/06 , C07K2319/00 , Y10S530/812
摘要： Bifunctional molecules and methods for their use in the production of binary or tripartite complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. The molecular weight of the bifunctional molecule is less than about 5000 daltons. In the methods, an effective amount of the bifunctional molecule is administered to the host. In certain embodiments the bifunctional molecule binds to the presenter protein and a drug target to produce a tripartite complex, while in other embodiments the bifunctional molecule binds to either the presenter protein or the drug target, but not both, to produce a binary complex The subject methods and compositions find use in a variety of therapeutic applications.
摘要翻译：提供了双功能分子及其在宿主生产二元或三方络合物中的用途。双功能分子是药物部分和展示蛋白质配体的缀合物。双功能分子的分子量小于约5000道尔顿。在该方法中，向宿主施用有效量的双功能分子。在某些实施方案中，双功能分子结合呈递者蛋白质和药物靶标以产生三部分复合物，而在其它实施方案中，双功能分子结合呈递者蛋白质或药物靶标而不是两者结合以产生二元复合物。受试者方法和组合物可用于各种治疗应用。

9. 发明授权

US06372712B1 Synthetic bifunctional molecules containing a drug moiety and presenter protein ligand 有权
标题翻译：含有药物部分和展示蛋白质配体的合成双功能分子
公开(公告)号：US06372712B1
公开(公告)日：2002-04-16
申请号：US09316932
申请日：1999-05-21
申请人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt William Vogel
发明人： Roger Briesewitz , Gerald R. Crabtree , Thomas Wandless , Gregory Thomas Ray , Kurt William Vogel
IPC分类号： A61K3800
CPC分类号： C12N9/90 , A61K38/00 , A61K47/54 , A61K47/552 , C07K5/1027 , C07K7/06 , C07K2319/00 , Y10S530/812
摘要： Bifunctional molecules and methods for their use in the production of binary complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. The molecular weight of the bifunctional molecule is preferably less than about 5000 daltons, and the drug moiety may have a molecular weight of from about 50 to 2000 daltons. The drug moiety and presenter protein ligand may be covalently linked directly or through a linking group. The drug moiety binds to a drug target such as a protein and the presenter protein ligand binds to a presenter protein that is not the drug target such as extracellular or intracellular protein. Presenter proteins include peptidyl prolyl isomerase (FKBP), Heat Shock Protein 90 (Hsp90), steroid hormone receptors, cytoskeletal proteins, albumin and vitamin receptors. When the presenter protein is FKBP, ligands include FK506, rapamycin and cyclosporin A which may have an introduced functional group such as hydroxyl, amino, carboxyl, aldehyde, carbonate, carbamate, azide, thiol or ester for attaching the drug moiety. In the methods of use, an effective amount of the bifunctional molecule is administered to the host. The bifunctional molecule binds to the presenter protein to produce a binary complex such that the drug exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The methods and bifunctional molecules find use in a variety of therapeutic applications.
摘要翻译：提供了双功能分子及其在宿主生产二元配合物中的应用。双功能分子是药物部分和展示蛋白质配体的缀合物。双功能分子的分子量优选小于约5000道尔顿，并且药物部分可具有约50至2000道尔顿的分子量。药物部分和展示蛋白配体可以直接或通过连接基团共价连接。药物部分结合于药物靶，例如蛋白质，并且呈递者蛋白质配体结合不是药物靶点的呈递蛋白，例如细胞外或细胞内蛋白质。载体蛋白包括肽基脯氨酰异构酶（FKBP），热休克蛋白90（Hsp90），类固醇激素受体，细胞骨架蛋白，白蛋白和维生素受体。当本发明蛋白是FKBP时，配体包括FK506，雷帕霉素和环孢菌素A，其可以具有引入的官能团，例如羟基，氨基，羧基，醛，碳酸酯，氨基甲酸酯，叠氮化物，硫醇或酯，用于连接药物部分。在使用方法中，向宿主施用有效量的双功能分子。双功能分子与展示蛋白结合以产生二元复合物，使得药物与相应的游离药物相比显示出改善的亲和性，特异性或选择性中的至少一种。方法和双功能分子可用于各种治疗应用。

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