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1. 发明公开

EP3302482A1 TANK-BINDING KINASE-1 PROTACS AND ASSOCIATED METHODS OF USE 审中-公开
标题翻译： TANK结合激酶-1保护和相关的使用方法
公开(公告)号：EP3302482A1
公开(公告)日：2018-04-11
申请号：EP16804646.4
申请日：2016-06-06
申请人： Arvinas, Inc. , Crew, Andrew, P. , Wang, Jing , Dong, Hanqing , Qian, Yimin , Siu, Kam , Ferraro, Caterina , Crews, Craig, M.
发明人： CREW, Andrew, P. , WANG, Jing , DONG, Hanqing , QIAN, Yimin , CREWS, Craig, M.
IPC分类号： A61K31/506 , C07D239/02
CPC分类号： A61K31/506 , A61K45/06 , A61K47/665 , A61K2300/00 , C07D413/04 , C07D417/04 , C07K5/06034
摘要： The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) TBK 1. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds TBK1 such that TBK1 is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of TBK1. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of TBK1.

2. 发明申请

WO2006073572A2 TREATMENT OF CONDITIONS CAUSED BY CALCIUM ABNORMALITIES 审中-公开
标题翻译：治疗由钙不正常引起的病症
公开(公告)号：WO2006073572A2
公开(公告)日：2006-07-13
申请号：PCT/US2005/041476
申请日：2005-11-15
申请人： YALE UNIVERSITY , CREWS, Craig, M. , QUINN, Stephanie, J.
发明人： CREWS, Craig, M. , QUINN, Stephanie, J.
IPC分类号： A61K31/366 , A61P13/12
CPC分类号： A61K31/366
摘要： In certain aspects, the invention relates to use of PKD2 agonists, such as triptolide and triptolide derivatives, to regulate calcium release. In other aspects, the invention relates to use of PKD2 agonists to treat or aid in the treatment of any condition in which a calcium channel, such as the gene product of PKD 1 and/or PKD2, is mutated; calcium signaling is abnormal; or both.
摘要翻译：在某些方面，本发明涉及使用PKD2激动剂，例如雷公藤内酯和雷公藤内酯衍生物来调节钙的释放。在其它方面，本发明涉及PKD2激动剂用于治疗或帮助治疗其中钙通道（例如PKD1和/或PKD2的基因产物）突变的任何病症的用途; 钙信号异常; 或两者。

3. 发明申请

WO2012078559A2 SMALL-MOLECULE HYDROPHOBIC TAGGING OF FUSION PROTEINS AND INDUCED DEGRADATION OF SAME 审中-公开
标题翻译：融合蛋白的小分子疏水性标记及其诱导的降解
公开(公告)号：WO2012078559A2
公开(公告)日：2012-06-14
申请号：PCT/US2011/063401
申请日：2011-12-06
申请人： YALE UNIVERSITY , CREWS, Craig, M. , TAE, Hyun, Seop , SCHNEEKLOTH, Ashley, R. , NEKLESA, Taavi , SUNDBERG, Thomas
发明人： CREWS, Craig, M. , TAE, Hyun, Seop , SCHNEEKLOTH, Ashley, R. , NEKLESA, Taavi , SUNDBERG, Thomas
IPC分类号： C07K17/02 , A61K31/708 , A61K31/7076 , A61K31/66 , A61P31/00
CPC分类号： G01N33/573 , A61K47/48015 , A61K47/52 , C07K1/13 , C07K2319/20 , C07K2319/95 , C12N9/14 , G01N33/5008 , G01N2500/10
摘要： The present invention relates to the ability to regulate any protein of interest in living systems with small molecules. In particular, the present invention relates to the discovery that appending a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. An aspect of the present invention relates to bifunctional small molecules that bind a number of proteins, including, for example, a self-labeling tag such as bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with a hydrophobic moiety (e.g. an adamantyl moiety) was effected and the tagging induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. The present invention also demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
摘要翻译：本发明涉及在具有小分子的生物体系中调节目的蛋白质的能力。特别地，本发明涉及在蛋白质表面附加疏水部分的发现，可以模拟蛋白质的部分变性状态，从而使细胞质量控制机制引起其蛋白酶体降解。本发明的一个方面涉及结合许多蛋白质的双功能小分子，包括例如自标记标签如细菌脱卤酶（HaloTag蛋白）并在其表面上呈现疏水基团。实现了具有疏水部分（例如金刚烷基部分）的HaloTag蛋白的疏水标签，并且标记诱导细胞培养物中细胞溶质，异戊二烯化和跨膜融合蛋白的降解。本发明还通过降解斑马鱼胚胎中表达的蛋白质和通过抑制小鼠中的RasG12V驱动的肿瘤进展来证明疏水性标签的体内实用性。因此，HaloTag融合蛋白的疏水性标签提供了对任何目标蛋白质的小分子控制，使其成为验证疾病模型中潜在药物靶点的理想系统。

4. 发明申请

WO2007021628A3 TARGET AND ASSAY FOR LEAD COMPOUNDS FOR POLYCYSTIC KIDNEY DISEASE 审中-公开
标题翻译：用于多科性感冒疾病的铅化合物的目标和测定
公开(公告)号：WO2007021628A3
公开(公告)日：2007-09-20
申请号：PCT/US2006030671
申请日：2006-08-09
申请人： UNIV YALE , SOMLO STEFAN , CREWS CRAIG M , QUINN STEPHANIE J
发明人： SOMLO STEFAN , CREWS CRAIG M , QUINN STEPHANIE J
IPC分类号： G01N33/50
CPC分类号： G01N33/6872 , C07K14/47 , G01N33/6893 , G01N2500/00
摘要： Described herein are therapeutic strategies (methods and compositions) useful for treating conditions in which cilia are affected and which manifest with cysts and/or fibrosis, such as conditions in which the kidney, pancreas, liver and/or spleen are affected and contain cysts. Particular embodiments described herein are therapeutic strategies in which PC-2 agonists, particularly agonists (calcium channel agonists) that target PC-2 directly and/or selectively, are administered to individuals with mutations in PKDl, in order to alter the course of polycystic kidney disease, particularly ADPKD.
摘要翻译：本文描述了治疗策略（方法和组合物），其可用于治疗其中纤毛受到影响并且表现为囊肿和/或纤维化的病症的病症，例如肾脏，胰腺，肝脏和/或脾脏受影响并含有囊肿的病症。本文描述的具体实施方案是将靶向PC-2直接和/或选择性的PC-2激动剂，特别是激动剂（钙通道激动剂）施用于具有PKD1突变的个体的治疗策略，以改变多囊肾的过程疾病，特别是ADPKD。

5. 发明申请

WO2005111008A2 COMPOUNDS FOR ENZYME INHIBITION 审中-公开
标题翻译：用于酶抑制的化合物
公开(公告)号：WO2005111008A2
公开(公告)日：2005-11-24
申请号：PCT/US2005/016335
申请日：2005-05-09
申请人： PROTEOLIX, INC. , SMYTH, Mark, S. , LAIDIG, Guy, J. , BORCHARDT, Ronald, T. , BUNIN, Barry, A. , CREWS, Craig, M. , MUSSER, John, H. , SHENK, Kevin, D. , RADEL, Peggy, A.
发明人： SMYTH, Mark, S. , LAIDIG, Guy, J. , BORCHARDT, Ronald, T. , BUNIN, Barry, A. , CREWS, Craig, M. , MUSSER, John, H. , SHENK, Kevin, D. , RADEL, Peggy, A.
IPC分类号： C07D303/00
CPC分类号： C07K5/0812 , C07K5/06034 , C07K5/0827 , Y02A50/412
摘要： Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsinlike activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.
摘要翻译：包括含杂原子的三元环的基于肽的化合物有效地选择性地抑制N末端亲核试剂（Ntn）水解酶的比活性。具有多种活性的那些Ntn的活性可被所描述的化合物差别地抑制。例如，本发明化合物可以选择性地抑制20S蛋白酶体的胰凝乳蛋白酶样活性。肽类化合物包括环氧化物或氮丙啶，并且在N-末端官能化。除了其它治疗用途之外，预期基于肽的化合物显示抗炎性质和抑制细胞增殖。

6. 发明申请

WO2007021628A9 TARGET AND ASSAY FOR LEAD COMPOUNDS FOR POLYCYSTIC KIDNEY DISEASE 审中-公开
标题翻译：多囊肾病铅化合物的靶向与检测
公开(公告)号：WO2007021628A9
公开(公告)日：2007-05-03
申请号：PCT/US2006030671
申请日：2006-08-09
申请人： UNIV YALE , SOMLO STEFAN , CREWS CRAIG M , QUINN STEPHANIE J
发明人： SOMLO STEFAN , CREWS CRAIG M , QUINN STEPHANIE J
IPC分类号： G01N33/50
CPC分类号： G01N33/6872 , C07K14/47 , G01N33/6893 , G01N2500/00
摘要： Described herein are therapeutic strategies (methods and compositions) useful for treating conditions in which cilia are affected and which manifest with cysts and/or fibrosis, such as conditions in which the kidney, pancreas, liver and/or spleen are affected and contain cysts. Particular embodiments described herein are therapeutic strategies in which PC-2 agonists, particularly agonists (calcium channel agonists) that target PC-2 directly and/or selectively, are administered to individuals with mutations in PKDl, in order to alter the course of polycystic kidney disease, particularly ADPKD.
摘要翻译：本文描述了用于治疗其中纤毛受影响并表现出囊肿和/或纤维化的病症（例如其中肾脏，胰腺，肝脏和/或脾脏受到影响并且包含囊肿的病症）的治疗策略（方法和组合物）。本文描述的具体实施方案是治疗策略，其中将PC-2激动剂，特别是直接和/或选择性靶向PC-2的激动剂（钙通道激动剂）给予PKD1突变的个体，以改变多囊肾疾病，特别是ADPKD。

7. 发明申请

WO2006073572A3 TREATMENT OF CONDITIONS CAUSED BY CALCIUM ABNORMALITIES 审中-公开
标题翻译：治疗由钙不正常引起的病症
公开(公告)号：WO2006073572A3
公开(公告)日：2006-08-31
申请号：PCT/US2005041476
申请日：2005-11-15
申请人： UNIV YALE , CREWS CRAIG M , QUINN STEPHANIE J
发明人： CREWS CRAIG M , QUINN STEPHANIE J
IPC分类号： A61K31/366 , A61P13/12
CPC分类号： A61K31/366
摘要： In certain aspects, the invention relates to use of PKD2 agonists, such as triptolide and triptolide derivatives, to regulate calcium release. In other aspects, the invention relates to use of PKD2 agonists to treat or aid in the treatment of any condition in which a calcium channel, such as the gene product of PKD 1 and/or PKD2, is mutated; calcium signaling is abnormal; or both, such as polycystic kidney disease.
摘要翻译：在某些方面，本发明涉及使用PKD2激动剂，例如雷公藤内酯和雷公藤内酯衍生物来调节钙的释放。在其它方面，本发明涉及PKD2激动剂用于治疗或帮助治疗其中钙通道（例如PKD1和/或PKD2的基因产物）突变的任何病症的用途; 钙信号异常; 或两者，如多囊肾病。

8. 发明申请

WO2005111008A3 COMPOUNDS FOR ENZYME INHIBITION 审中-公开
标题翻译：用于酶抑制的化合物
公开(公告)号：WO2005111008A3
公开(公告)日：2006-03-16
申请号：PCT/US2005016335
申请日：2005-05-09
申请人： PROTEOLIX INC , SMYTH MARK S , LAIDIG GUY J , BORCHARDT RONALD T , BUNIN BARRY A , CREWS CRAIG M , MUSSER JOHN H , SHENK KEVIN D , RADEL PEGGY A
发明人： SMYTH MARK S , LAIDIG GUY J , BORCHARDT RONALD T , BUNIN BARRY A , CREWS CRAIG M , MUSSER JOHN H , SHENK KEVIN D , RADEL PEGGY A
IPC分类号： C07K5/087 , A61K31/335 , A61K38/06 , C07D303/32 , C07D409/12 , C07D413/12 , C07K5/027 , C07K5/06 , C07K5/062 , C07K5/078 , C07K5/08
CPC分类号： C07K5/0812 , C07K5/06034 , C07K5/0827
摘要： Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.
摘要翻译：包括含杂原子的三元环的基于肽的化合物有效地选择性地抑制N末端亲核试剂（Ntn）水解酶的比活性。具有多种活性的那些Ntn的活性可被所描述的化合物差别地抑制。例如，本发明化合物可以选择性地抑制20S蛋白酶体的胰凝乳蛋白酶样活性。肽类化合物包括环氧化物或氮丙啶，并且在N-末端官能化。除了其它治疗用途之外，预期基于肽的化合物显示抗炎性质和抑制细胞增殖。

9. 发明申请

WO2012078559A3 SMALL-MOLECULE HYDROPHOBIC TAGGING OF FUSION PROTEINS AND INDUCED DEGRADATION OF SAME 审中-公开
标题翻译：融合蛋白的小分子疏水标记及其诱导降解
公开(公告)号：WO2012078559A3
公开(公告)日：2012-12-06
申请号：PCT/US2011063401
申请日：2011-12-06
申请人： UNIV YALE , CREWS CRAIG M , TAE HYUN SEOP , SCHNEEKLOTH ASHLEY R , NEKLESA TAAVI , SUNDBERG THOMAS
发明人： CREWS CRAIG M , TAE HYUN SEOP , SCHNEEKLOTH ASHLEY R , NEKLESA TAAVI , SUNDBERG THOMAS
IPC分类号： C07K17/02 , A61K31/66 , A61K31/7076 , A61K31/708 , A61P31/00
CPC分类号： G01N33/573 , A61K47/48015 , A61K47/52 , C07K1/13 , C07K2319/20 , C07K2319/95 , C12N9/14 , G01N33/5008 , G01N2500/10
摘要： The present invention relates to the ability to regulate any protein of interest in living systems with small molecules. In particular, the present invention relates to the discovery that appending a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation. An aspect of the present invention relates to bifunctional small molecules that bind a number of proteins, including, for example, a self-labeling tag such as bacterial dehalogenase (HaloTag protein) and present a hydrophobic group on its surface. Hydrophobic tagging of the HaloTag protein with a hydrophobic moiety (e.g. an adamantyl moiety) was effected and the tagging induced the degradation of cytosolic, isoprenylated, and transmembrane fusion proteins in cell culture. The present invention also demonstrated the in vivo utility of hydrophobic tagging by degrading proteins expressed in zebrafish embryos and by inhibiting RasG12V-driven tumor progression in mice. Therefore, hydrophobic tagging of HaloTag fusion proteins affords small molecule control over any protein of interest, making it an ideal system for validating potential drug targets in disease models.
摘要翻译：本发明涉及用小分子调节活体系中感兴趣的任何蛋白质的能力。特别地，本发明涉及这样的发现，即将疏水部分附加到蛋白质的表面上可以模拟蛋白质的部分变性状态，从而使细胞质量控制机构引起其蛋白酶体降解。本发明的一个方面涉及结合许多蛋白质的双功能小分子，包括例如自标记标签如细菌脱卤素酶（HaloTag蛋白质）并且在其表面上呈现疏水基团。用疏水部分（例如金刚烷基部分）对HaloTag蛋白质进行疏水性标记，标记诱导细胞培养物中胞质，异丙基化和跨膜融合蛋白质的降解。本发明还通过降解在斑马鱼胚胎中表达的蛋白质和通过抑制小鼠中RasG12V驱动的肿瘤进展来证明疏水性标签的体内实用性。因此，HaloTag融合蛋白的疏水标签可以使小分子控制任何感兴趣的蛋白质，使其成为验证疾病模型中潜在药物靶点的理想系统。

10. 发明申请

WO2007021628A2 TARGET AND ASSAY FOR LEAD COMPOUNDS FOR POLYCYSTIC KIDNEY DISEASE 审中-公开
标题翻译：多囊肾病铅化合物的靶向与检测
公开(公告)号：WO2007021628A2
公开(公告)日：2007-02-22
申请号：PCT/US2006/030671
申请日：2006-08-09
申请人： YALE UNIVERSITY , SOMLO, Stefan , CREWS, Craig, M. , QUINN, Stephanie, J.
发明人： SOMLO, Stefan , CREWS, Craig, M. , QUINN, Stephanie, J.
IPC分类号： G01N33/50
CPC分类号： G01N33/6872 , C07K14/47 , G01N33/6893 , G01N2500/00
摘要： Described herein are therapeutic strategies (methods and compositions) useful for treating conditions in which cilia are affected and which manifest with cysts and/or fibrosis, such as conditions in which the kidney, pancreas, liver and/or spleen are affected and contain cysts. Particular embodiments described herein are therapeutic strategies in which PC-2 agonists, particularly agonists (calcium channel agonists) that target PC-2 directly and/or selectively, are administered to individuals with mutations in PKDl , in order to alter the course of polycystic kidney disease, particularly ADPKD.
摘要翻译：本文描述了用于治疗其中纤毛受到影响并表现出囊肿和/或纤维化的病症（例如其中肾脏，胰腺，肝脏和/或肝脏）的病症的治疗策略（方法和组合物）或脾脏受到影响并含有囊肿。本文描述的具体实施方案是治疗策略，其中PC-2激动剂，特别是直接和/或选择性靶向PC-2的激动剂（钙通道激动剂）以PKD1突变的形式施用给个体改变多囊肾病的病程，特别是ADPKD。

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