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1. 发明申请

WO2012040602A2 TARGETING MTOR SUBSTRATES IN TREATING PROLIFERATIVE DISEASES 审中-公开
标题翻译：靶向治疗增生性疾病的MTOR基质
公开(公告)号：WO2012040602A2
公开(公告)日：2012-03-29
申请号：PCT/US2011/053035
申请日：2011-09-23
申请人： PRESIDENT AND FELLOWS OF HARVARD COLLEGE , BLENIS, John , GYGI, Steven, P. , YU, Yonghao
发明人： BLENIS, John , GYGI, Steven, P. , YU, Yonghao
IPC分类号： G01N33/574
CPC分类号： C12Q1/485 , G01N33/5011 , G01N33/68 , G01N33/74 , G01N2333/4703
摘要： Some aspects of this invention relate to the identification of over 300 mTOR kinase targets by a comprehensive phosphoproteomics assay. Some aspects of this invention relate to targeting mTOR kinase targets, for example, Grb10, FOXK1, ZEB2, NDRG3, LARP1, SRPK2, CDK12, MIB1, or IBTK, in treating hyperproliferative disease. Some aspects of this invention relate to methods to determine the level of mTOR activity by measuring the level of phosphorylation of an mTOR targeted phosphorylation site, for example, a Grb10, FOXK1, ZEB2, NDRG3, LARP1, SRPK2, CDK12, MIB1, and/or IBTK phosphorylation site. Some aspects of this invention relate to methods for distinguishing different classes of mTOR activity in a cell based on phosphoproteomic analysis of mTOR-targeted proteins. Some aspects of this invention relate to the classification of a hyperproliferative disease based on phosphoproteomic analysis of mTOR-targeted proteins. Some aspects of this invention relate to the personalization of therapeutic methods for the treatment of hyperproliferative disease based on phosphoproteomics. Some aspects relate to therapeutic methods including administering to a subject an mTOR inhibitor, an mTOR inhibitor and an additional kinase inhibitor, or a dual inhibitor of mTOR and an additional kinase based on the phosphorylation levels of mTOR targets determined in the subject. Some aspects of this invention relate to the discovery that Grb10 is an mTOR-targeted tumor suppressor gene.
摘要翻译：本发明的一些方面涉及通过综合磷酸化蛋白质组学测定鉴定超过300个mTOR激酶靶标。本发明的一些方面涉及靶向mTOR激酶靶标，例如Grb10，FOXK1，ZEB2，NDRG3，LARP1，SRPK2，CDK12，MIB1或IBTK，以治疗过度增殖性疾病。本发明的一些方面涉及通过测量mTOR靶向磷酸化位点磷酸化水平，例如Grb10，FOXK1，ZEB2，NDRG3，LARP1，SRPK2，CDK12，MIB1和/ 或IBTK磷酸化位点。本发明的一些方面涉及基于mTOR靶向蛋白质的磷酸化蛋白质分析来区分细胞中不同类型的mTOR活性的方法。本发明的一些方面涉及基于mTOR靶向蛋白质的磷酸化蛋白质组学分析的过度增殖性疾病的分类。本发明的一些方面涉及基于磷酸化蛋白质学治疗过度增殖性疾病的治疗方法的个性化。一些方面涉及治疗方法，包括向受试者施用mTOR抑制剂，mTOR抑制剂和另外的激酶抑制剂，或基于在受试者中确定的mTOR靶标的磷酸化水平的mTOR的双重抑制剂和另外的激酶。本发明的一些方面涉及Grb10是mTOR靶向的肿瘤抑制基因的发现。

2. 发明申请

WO2005007090A3 INHIBITORS OF THE MAP KINASE PATHWAY 审中-公开
标题翻译： MAP激活途径的抑制剂
公开(公告)号：WO2005007090A3
公开(公告)日：2009-04-09
申请号：PCT/US2004021514
申请日：2004-07-02
申请人： HARVARD COLLEGE , BLENIS JOHN , MURPHY LEON O
发明人： BLENIS JOHN , MURPHY LEON O
IPC分类号： C12N15/00 , A61K20060101 , C12N5/00 , G01N33/50 , G01N33/574 , G01N33/68
CPC分类号： G01N33/5011 , A61K47/62 , G01N33/5041 , G01N33/57496 , G01N33/6893 , G01N2333/91205 , G01N2500/02
摘要： MAP kinases (e.g., ERKI/2) phosphorylate a variety of target proteins including, for example, several immediate early gene products (e.g., Fos, Myc, and Jun family proteins). Certain phosphorylation reactions require binding of the MAP kinase to the DEF domain of the target protein. Inhibitors that block this interaction may be useful therapeutics for human disease, including as antineoplastic agents. Also disclosed are screening assays useful for identifying compounds that inhibit the MAP kinase-DEF domain interaction.
摘要翻译： MAP激酶（例如，ERKI / 2）磷酸化各种靶蛋白，包括例如若干立即早期基因产物（例如Fos，Myc和Jun家族蛋白）。某些磷酸化反应需要MAP激酶与靶蛋白的DEF结构域的结合。阻断这种相互作用的抑制剂可能是人类疾病的有用治疗剂，包括作为抗肿瘤剂。还公开了用于鉴定抑制MAP激酶-DF结构域相互作用的化合物的筛选测定法。

3. 发明申请

WO2015123377A1 P13K-MTORC1-S6K1 SIGNALING PATHWAY BIOMARKERS PREDICTIVE OF ANTI-CANCER RESPONSES 审中-公开
标题翻译： P13K-MTORC1-S6K1信号通路生物标志物预防癌症反应
公开(公告)号：WO2015123377A1
公开(公告)日：2015-08-20
申请号：PCT/US2015/015544
申请日：2015-02-12
申请人： DANA-FARBER CANCER INSTITUTE, INC. , ROBERTS, Thomas, M. , TONG, Haoxuan , ZHAO, Jean, J. , BLENIS, John
发明人： ROBERTS, Thomas, M. , TONG, Haoxuan , ZHAO, Jean, J. , BLENIS, John
IPC分类号： C12Q1/68
CPC分类号： G01N33/5011 , A61K31/58 , A61K45/06 , C12Q1/6886 , C12Q2600/106 , C12Q2600/118 , C12Q2600/136 , C12Q2600/156 , C12Q2600/158 , G01N33/5088 , G01N33/57492 , G01N2333/91215 , G01N2500/10
摘要： The present invention is based, in part, on the identification of novel FI.3K- mTORCI-S6K 1 signaling pathway biomarkers predictive of responsiveness to anti-cancer therapies.
摘要翻译：本发明部分地基于鉴定预测对抗癌疗法的反应性的新型FI.3K-mTORCI-S6K1信号通路生物标志物。

4. 发明申请

WO2012040602A3 TARGETING MTOR SUBSTRATES IN TREATING PROLIFERATIVE DISEASES 审中-公开
标题翻译：靶向治疗增生性疾病的MTOR基质
公开(公告)号：WO2012040602A3
公开(公告)日：2012-12-06
申请号：PCT/US2011053035
申请日：2011-09-23
申请人： HARVARD COLLEGE , BLENIS JOHN , GYGI STEVEN P , YU YONGHAO
发明人： BLENIS JOHN , GYGI STEVEN P , YU YONGHAO
IPC分类号： G01N33/574
CPC分类号： C12Q1/485 , G01N33/5011 , G01N33/68 , G01N33/74 , G01N2333/4703
摘要： Provided are over 300 mTOR kinase targets identified by a comprehensive phosphoproteomics assay. Methods of targeting mTOR kinase targets, methods to determine the level of mTOR activity by measuring the level of phosphorylation of an mTOR targeted phosphorylation site, methods for distinguishing different classes of mTOR activity in a cell based on phosphoproteomic analysis ofmTOR-targeted proteins are also provided. Also provided is the classification of a hyperproliferative disease based on phosphoproteomic analysis ofmTOR-targeted proteins, as well as the personalization of therapeutic methods for the treatment of hyperproliferative disease based on phosphoproteomics. Also provided are therapeutic methods including administering to a subject an mTOR inhibitor, an mTOR inhibitor and an additional kinase inhibitor, or a dual inhibitor ofmTOR and an additional kinase based on the phosphorylation levels of mTOR targets determined in the subject. Some aspects of this invention relate to the discovery that GrblO is an mTOR-targeted tumor suppressor gene.
摘要翻译：提供了通过综合磷酸化蛋白质测定法鉴定的超过300个mTOR激酶靶标。靶向mTOR激酶靶标的方法，通过测量mTOR靶向磷酸化位点的磷酸化水平来确定mTOR活性水平的方法，还提供了基于对靶向蛋白质的磷酸化蛋白质分析来区分细胞中不同种类的mTOR活性的方法。还提供了基于对靶向蛋白质的磷酸化蛋白质组学分析的过度增殖性疾病的分类，以及基于磷酸化蛋白质治疗过度增殖性疾病的治疗方法的个性化。还提供了治疗方法，包括向受试者施用mTOR抑制剂，mTOR抑制剂和另外的激酶抑制剂，或基于在受试者中确定的mTOR靶标的磷酸化水平的mTOR的双重抑制剂和另外的激酶。本发明的一些方面涉及GrblO是mTOR靶向的肿瘤抑制基因的发现。

5. 发明申请

WO2006091701A3 METHODS AND COMPOSITIONS FOR MODULATING CELL DEATH WITH SURVIVAL-OR DEATH KINASES OR PHOSPHATASES 审中-公开
标题翻译：用于调节存活或死亡动物或磷酸酶的细胞死亡的方法和组合物
公开(公告)号：WO2006091701A3
公开(公告)日：2007-07-26
申请号：PCT/US2006006346
申请日：2006-02-22
申请人： HARVARD COLLEGE , MACKEIGAN JEFFREY P , MURPHY LEON O , BLENIS JOHN
发明人： MACKEIGAN JEFFREY P , MURPHY LEON O , BLENIS JOHN
IPC分类号： G01N33/50 , C12Q1/42 , C12Q1/48
CPC分类号： G01N33/5017 , C12Q1/42 , C12Q1/485 , G01N2333/91215 , G01N2500/00 , G01N2510/00
摘要： The invention relates to methods for modulating cell death and cell survival and for modulating the sensitivity of cells towards agents that modulate cell death or cell survival. The invention also relates to the identification of kinases and phosphatases that promote cell survival or cell death. The invention further relates to methods for screening compounds that modulate the activity, expression and/or protein-protein interactions of cell survival or cell death-promoting kinases and phosphatases. Accordingly, kinases and/or phosphatases that modulate cell proliferation and death may serve as therapeutic targets for the development of new cancer treatments.
摘要翻译：本发明涉及调节细胞死亡和细胞存活并调节细胞对调节细胞死亡或细胞存活的药物敏感性的方法。本发明还涉及促进细胞存活或细胞死亡的激酶和磷酸酶的鉴定。本发明还涉及用于筛选调节细胞存活或细胞死亡促进激酶和磷酸酶的活性，表达和/或蛋白质 - 蛋白质相互作用的化合物的方法。因此，调节细胞增殖和死亡的激酶和/或磷酸酶可以作为开发新的癌症治疗的治疗靶点。

6. 发明申请

WO2006091701A2 METHODS AND COMPOSITIONS FOR MODULATING CELL DEATH WITH SURVIVAL-OR DEATH KINASES OR PHOSPHATASES 审中-公开
标题翻译：用于调节细胞死亡与死亡或死亡细胞或磷酸酶的方法和组合物
公开(公告)号：WO2006091701A2
公开(公告)日：2006-08-31
申请号：PCT/US2006/006346
申请日：2006-02-22
申请人： PRESIDENT AND FELLOWS OF HARVARD COLLEGE , MACKEIGAN, Jeffrey, P. , MURPHY, Leon, O. , BLENIS, John
发明人： MACKEIGAN, Jeffrey, P. , MURPHY, Leon, O. , BLENIS, John
CPC分类号： G01N33/5017 , C12Q1/42 , C12Q1/485 , G01N2333/91215 , G01N2500/00 , G01N2510/00
摘要： The invention relates to methods for modulating cell death and cell survival and for modulating the sensitivity of cells towards agents that modulate cell death or cell survival. The invention also relates to the identification of kinases and phosphatases that promote cell survival or cell death. The invention further relates to methods for screening compounds that modulate the activity, expression and/or protein-protein interactions of cell survival or cell death-promoting kinases and phosphatases. Accordingly, kinases and/or phosphatases that modulate cell proliferation and death may serve as therapeutic targets for the development of new cancer treatments.
摘要翻译：本发明涉及调节细胞死亡和细胞存活并调节细胞对调节细胞死亡或细胞存活的药物的敏感性的方法。本发明还涉及促进细胞存活或细胞死亡的激酶和磷酸酶的鉴定。本发明还涉及用于筛选调节细胞存活或细胞死亡促进激酶和磷酸酶的活性，表达和/或蛋白质 - 蛋白质相互作用的化合物的方法。因此，调节细胞增殖和死亡的激酶和/或磷酸酶可以作为开发新的癌症治疗的治疗靶点。

7. 发明申请

WO2005007090A2 INHIBITORS OF THE MAP KINASE PATHWAY 审中-公开
标题翻译： MAP激活途径的抑制剂
公开(公告)号：WO2005007090A2
公开(公告)日：2005-01-27
申请号：PCT/US2004/021514
申请日：2004-07-02
申请人： PRESIDENT AND FELLOWS OF HARVARD COLLEGE , BLENIS, John , MURPHY, Leon, O.
发明人： BLENIS, John , MURPHY, Leon, O.
IPC分类号： A61K
CPC分类号： G01N33/5011 , A61K47/62 , G01N33/5041 , G01N33/57496 , G01N33/6893 , G01N2333/91205 , G01N2500/02
摘要： MAP kinases (e.g., ERKI/2) phosphorylate a variety of target proteins including, for example, several immediate early gene products (e.g., Fos, Myc, and Jun family proteins). Certain phosphorylation reactions require binding of the MAP kinase to the DEF domain of the target protein. Inhibitors that block this interaction may be useful therapeutics for human disease, including as antineoplastic agents. Also disclosed are screening assays useful for identifying compounds that inhibit the MAP kinase-DEF domain interaction.
摘要翻译： MAP激酶（例如，ERKI / 2）磷酸化各种靶蛋白，包括例如若干立即早期基因产物（例如Fos，Myc和Jun家族蛋白）。某些磷酸化反应需要MAP激酶与靶蛋白的DEF结构域的结合。阻断这种相互作用的抑制剂可能是人类疾病的有用治疗剂，包括作为抗肿瘤剂。还公开了用于鉴定抑制MAP激酶-DF结构域相互作用的化合物的筛选测定法。

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