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1. 发明授权

US07259142B2 Redox-stable, non-phosphorylated cyclic peptide inhibitors of SH2 domain binding to target protein, conjugates thereof, compositions and methods of synthesis and use 有权
标题翻译：与靶蛋白结合的SH2结构域的氧化还原稳定的非磷酸化环肽抑制剂，其结合物，组合物和合成和使用方法
公开(公告)号：US07259142B2
公开(公告)日：2007-08-21
申请号：US11224819
申请日：2005-09-13
申请人： Peter P Roller , Ya-Qui Long , Feng-Di T. Lung , C. Richter King , Dajun Yang , Johannes H. Voigt
发明人： Peter P Roller , Ya-Qui Long , Feng-Di T. Lung , C. Richter King , Dajun Yang , Johannes H. Voigt
IPC分类号： A61K38/12
CPC分类号： C07K7/06 , A61K38/00 , C07K7/56
摘要： A compound of formula: in which (i) aa1 is Adi and aa4 is Glu or (ii) each of aa1 and aa4 is Adi, L is sulfur, sulfoxide, oxygen or methylene, which compound (and its conjugates) bind to an SH2 domain in a protein comprising an SH2 domain, is non-phosphorylated, is redox-stable in vivo, is characterized by an IC50 in vivo of less than about 4.0 μM with respect to the SH2 domain in Grb2, and, upon binding to the SH2 domain of Grb2, has a turn conformation. A conjugate comprising a compound as described above and a carrier agent, a composition comprising (i) a compound or a conjugate as described above and (ii) a carrier, a method of inhibiting binding of an SH2 domain in a protein comprising an SH2 domain to a target protein in an animal, wherein the SH2 domain is contacted with a target protein-binding inhibiting effective amount of a compound or a conjugate as described above, and a method of synthesizing such conjugates.
摘要翻译：下式化合物：其中（i）aa 1是Adi，aa 4是Glu或（ii）aa 1和a a各自独立地选自 Ad1，L是硫，亚砜，氧或亚甲基，该化合物（及其缀合物）与包含SH2结构域的蛋白质中的SH2结构域结合，未被磷酸化，是氧化还原稳定的在体内，相对于Grb2中的SH2结构域，其体内IC 50小于约4.0μM，并且在结合到Grb2的SH2结构域时具有转向构象。包含如上所述的化合物和载体的缀合物，包含（i）如上所述的化合物或缀合物和（ii）载体的组合物，抑制包含SH2结构域的蛋白质中SH2结构域结合的方法涉及一种动物中的靶蛋白，其中SH2结构域与靶蛋白结合抑制有效量的上述化合物或结合物接触，以及合成这种缀合物的方法。

2. 发明授权

US06951915B2 Redox-stable, non-phosphorylated cyclic peptide inhibitors of SH2 domain binding to target protein, conjugates thereof, compositions and methods of synthesis and use 有权
标题翻译：与靶蛋白结合的SH2结构域的氧化还原稳定的非磷酸化环肽抑制剂，其结合物，组合物和合成和使用方法
公开(公告)号：US06951915B2
公开(公告)日：2005-10-04
申请号：US09998350
申请日：2001-11-30
申请人： Peter P. Roller , Ya-Qiu Long , Feng-Di T. Lung , C. Richter King , Dajun Yang
发明人： Peter P. Roller , Ya-Qiu Long , Feng-Di T. Lung , C. Richter King , Dajun Yang
IPC分类号： A61K38/00 , C07K7/06 , C07K7/56 , C07K7/00 , A61K31/00 , C07K7/50
CPC分类号： C07K7/06 , A61K38/00 , C07K7/56
摘要： A compound of formula: in which L is sulfur, sulfoxide, oxygen or methylene, and a compound of formula: in which (i) aa1 is Adi and aa4 is Glu or (ii) each of aa1 and aa4 is Adi, L is sulfur, sulfoxide, oxygen or methylene, which compounds (and their conjugates) bind to an SH2 domain in a protein comprising an SH2 domain, are non-phosphorylated, are redox-stable in vivo, are characterized by an IC50 in vivo of less than about 4.0 μM with respect to the SH2 domain in Grb2, and, upon binding to the SH2 domain of Grb2, have a turn conformation. A conjugate comprising a compound as described above and a carrier agent, a composition comprising (i) a compound or a conjugate as described above and (ii) a carrier, a method of inhibiting binding of an SH2 domain in a protein comprising an SH2 domain to a target protein in an animal, wherein the SH2 domain is contacted with a target protein-binding inhibiting effective amount of a compound or a conjugate as described above, and a method of synthesizing such conjugates.
摘要翻译：下式的化合物：其中L是硫，亚砜，氧或亚甲基，以及下式的化合物：其中（i）aa 1是Adi和aa 4是 Glu或（ii）aa 1和a 4中的每一个为Adi，L为硫，亚砜，氧或亚甲基，该化合物（及其共轭物）与SH2结合包含SH2结构域的未被磷酸化，在体内氧化还原稳定的蛋白质的结构域的特征在于体内相对于Grb2中的SH2结构域的小于约4.0μM的IC 50 并且在与Grb2的SH2结构域结合时具有转向构象。包含如上所述的化合物和载体的缀合物，包含（i）如上所述的化合物或缀合物和（ii）载体的组合物，抑制包含SH2结构域的蛋白质中SH2结构域结合的方法涉及一种动物中的靶蛋白，其中SH2结构域与靶蛋白结合抑制有效量的上述化合物或结合物接触，以及合成这种缀合物的方法。

3. 发明申请

US20080031812A1 REDOX-STABLE, NON-PHOSPHORYLATED CYCLIC PEPTIDE INHIBITORS OF SH2 DOMAIN BINDING TO TARGET PROTEIN, CONJUGATES, THEREOF, COMPOSITIONS AND METHODS OF SYNTHESIS AND USE 审中-公开
标题翻译：抗氧化稳定性，SH2结合蛋白的非磷酸化循环肽抑制剂与靶向蛋白质，其结合物，组合物及其合成和使用方法
公开(公告)号：US20080031812A1
公开(公告)日：2008-02-07
申请号：US11838427
申请日：2007-08-14
申请人： Peter Roller , Ya-Qiu Long , Feng-Di T. Lung , C. Richter King , Dajun Yang , Johannes Voigt
发明人： Peter Roller , Ya-Qiu Long , Feng-Di T. Lung , C. Richter King , Dajun Yang , Johannes Voigt
IPC分类号： A61K38/12 , A61K51/00 , A61P35/00
CPC分类号： C07K7/56 , A61K38/00 , A61K47/64 , C07K7/06
摘要： A compound of formula: in which (i) aa1 is Adi and aa4 is Glu or (ii) each of aa1 and aa4 is Adi, L is sulfur, sulfoxide, oxygen or methylene, which compound (and its conjugates) bind to an SH2 domain in a protein comprising an SH2 domain, is non-phosphorylated, is redox-stable in vivo, is characterized by an IC50 in vivo of less than about 4.0 μM with respect to the SH2 domain in Grb2, and, upon binding to the SH2 domain of Grb2, has a turn conformation. A conjugate comprising a compound as described above and a carrier agent, a composition comprising (i) a compound or a conjugate as described above and (ii) a carrier, a method of inhibiting binding of an SH2 domain in a protein comprising an SH2 domain to a target protein in an animal, wherein the SH2 domain is contacted with a target protein-binding inhibiting effective amount of a compound or a conjugate as described above, and a method of synthesizing such conjugates.
摘要翻译：下式化合物：其中（i）aa 1是Adi，aa 4是Glu或（ii）aa 1和a a各自独立地选自 Ad1，L是硫，亚砜，氧或亚甲基，该化合物（及其缀合物）与包含SH2结构域的蛋白质中的SH2结构域结合，未被磷酸化，是氧化还原稳定的在体内，相对于Grb2中的SH2结构域，其体内IC 50小于约4.0μM，并且在结合到Grb2的SH2结构域时具有转向构象。包含如上所述的化合物和载体的缀合物，包含（i）如上所述的化合物或缀合物和（ii）载体的组合物，抑制包含SH2结构域的蛋白质中SH2结构域结合的方法涉及一种动物中的靶蛋白，其中SH2结构域与靶蛋白结合抑制有效量的上述化合物或结合物接触，以及合成这种缀合物的方法。

4. 发明申请

US20090175869A1 Pulsatile Dosing of Gossypol for Treatment of Disease 审中-公开
标题翻译：棉酚用于治疗疾病的脉动剂量
公开(公告)号：US20090175869A1
公开(公告)日：2009-07-09
申请号：US12332039
申请日：2008-12-10
申请人： Jon T. Holmlund , Mel Sorensen , Lance Leopold , Dajun Yang
发明人： Jon T. Holmlund , Mel Sorensen , Lance Leopold , Dajun Yang
IPC分类号： A61K39/395 , A61K31/12 , A61K31/337 , A61K31/454 , A61K33/24 , A61K31/282 , A61K31/517 , A61K31/437 , A61P35/00
CPC分类号： A61K31/12 , A61K31/282 , A61K31/337 , A61K31/437 , A61K31/454 , A61K31/517 , A61K45/06 , A61K2300/00
摘要： This invention relates to pulsatile dose administration of gossypol, a gossypol-related compound or pharmaceutical compositions thereof for treating diseases, disorders and conditions responsive to gossypol or gossypol-related compound, inhibiting the activity of anti-apoptotic Bcl-2 family proteins, inducing apoptosis in cells and increasing the sensitivity of cells to inducers of apoptosis.
摘要翻译：本发明涉及棉酚的脉动剂量施用，棉酚相关化合物或其药物组合物，用于治疗对棉酚或棉酚相关化合物有反应的疾病，病症和病症，抑制抗凋亡Bcl-2家族蛋白的活性，诱导细胞凋亡并增加细胞对细胞凋亡诱导因子的敏感性。

5. 发明申请

US20090092684A1 SMALL MOLECULE ANTAGONISTS OF BCL-2 FAMILY PROTEINS 有权
公开(公告)号：US20090092684A1
公开(公告)日：2009-04-09
申请号：US12242380
申请日：2008-09-30
申请人： Shaomeng Wang , Dajun Yang , Liang Xu
发明人： Shaomeng Wang , Dajun Yang , Liang Xu
IPC分类号： A61K31/12 , A61P35/00 , A61K33/24 , A61K31/337
CPC分类号： A61K31/11 , A61K45/06 , A61K2300/00
摘要： The present invention relates to naturally occurring and chemically synthesized small molecule antagonists of Bcl-2 family proteins. In particular, the present invention provides gossypol compounds (e.g., isomers, enantiomers, racemic compounds, metabolites, derivatives, pharmaceutically acceptable salts, in combination with acids or bases, and the like) and methods of using these compounds as antagonists of the anti-apoptotic effects of Bcl-2 family member proteins (e.g., Bcl-2, Bcl-XL, and the like). The present invention also provides compositions comprising gossypol compounds and optionally one or more additional therapeutic agents (e.g., anticancer/chemotherapeutic agents). The present invention also provides methods for treating diseases and pathologies (e.g., neoplastic diseases) comprising administering a composition comprising gossypol compounds and optionally one or more additional therapeutic agents (e.g., anticancer/chemotherapeutic agents) and/or techniques (e.g., radiation therapies, surgical interventions, and the like) to a subject or in vitro cells, tissues, and organs.

6. 发明授权

US07825216B2 Phenylanine derivatives 有权
标题翻译：苯胺衍生物
公开(公告)号：US07825216B2
公开(公告)日：2010-11-02
申请号：US11749499
申请日：2007-05-16
申请人： Terrence R. Burke, Jr. , Yang Gao , Zhu-jun Yao , Dajun Yang
发明人： Terrence R. Burke, Jr. , Yang Gao , Zhu-jun Yao , Dajun Yang
IPC分类号： C07K2/00
CPC分类号： C07K5/0819 , A61K38/00 , C07C271/22 , C07D265/32 , C07K5/0812 , C07K5/0827
摘要： The present invention provides phenylalanine derivatives that inhibit SH2 domain binding with a phosphoprotein. These derivatives include compounds of the formula: W—Y-(AA)n-Z wherein n is 0 to 15; Y is a phenylalanyl radical having a phenyl ring, an amine end, and a carboxyl end, the phenyl ring having one or more substituents, e.g., hydroxyl, carboxyl, formyl, carboxyalkyl, carboxyalkyloxy, dicarboxyalkyl, dicarboxyalkyloxy, dicarboxyhaloalkyl, dicarboxyhaloalkyloxy, and phosphonoalkyl, or phosphonohaloalkyl; W is a moiety attached to the nitrogen of Y and is, e.g., alkylcarbonyl, oxalyl, alkylaminooxalyl, arylaminooxalyl, arylalkylaminooxalyl, or alkoxyoxalyl; AA is an amino acid, the amine end of which is attached to the carboxyl end of Y; and Z is an arylalkylamino or arylheterocyclyl alkylamino; or a salt thereof; with the proviso that W is not arylalkylamino when the phenyl ring of phenylalanyl contains a phosphonoalkyl or phosphonohaloalkyl substituent at a position para to the alkylamido group and the ortho and meta positions are unsubstituted. The present invention further provides precursors suitable for preparing the phenylalanine derivatives and a method for the preparation of the precursors. The present invention further provides conjugates comprising a precursor and a conjugant that are covalently linked. These conjugates have biological and/or pharmacological properties.
摘要翻译：本发明提供抑制与磷蛋白结合的SH2结构域的苯丙氨酸衍生物。这些衍生物包括下式的化合物：其中n为0至15的W-Y-（AA）n-Z; Y是具有苯环，胺末端和羧基端的苯丙氨酰基，苯环具有一个或多个取代基，例如羟基，羧基，甲酰基，羧基烷基，羧基烷氧基，二羧基烷基，二羧基烷氧基，二羧基卤代烷基，二羧基卤代烷氧基和膦酰基烷基，或膦酰卤代烷基; W是连接到Y的氮的部分，例如烷基羰基，草酰基，烷基氨基草酰基，芳基氨基草酰基，芳基烷基氨基草酰基或烷氧基草酰基; AA是氨基酸，其末端连接到Y的羧基末端; Z是芳基烷基氨基或芳基杂环基烷基氨基; 或其盐; 条件是当苯丙氨酰基的苯环在烷基酰氨基的对位位置含有膦酰基烷基或膦酰卤代烷基取代基时，W不是芳烷基氨基，邻位和间位是未取代的。本发明还提供适用于制备苯丙氨酸衍生物的前体和前体的制备方法。本发明进一步提供包含共价连接的前体和共轭物的缀合物。这些缀合物具有生物学和/或药理学性质。

7. 发明申请

US20100069344A1 SMALL MOLECULE ANTAGONISTS OF BCL2 FAMILY PROTEINS 审中-公开
标题翻译： BCL2家族蛋白的小分子拮抗剂
公开(公告)号：US20100069344A1
公开(公告)日：2010-03-18
申请号：US12609761
申请日：2009-10-30
申请人： Shaomeng Wang , Dajun Yang , Liang Xu
发明人： Shaomeng Wang , Dajun Yang , Liang Xu
IPC分类号： A61K31/573 , A61P35/00
CPC分类号： A61K31/11 , A61K45/06 , A61K2300/00
摘要： The present invention relates to naturally occurring and chemically synthesized small molecule antagonists of Bcl-2 family proteins. In particular, the present invention provides gossypol compounds (e.g., isomers, enantiomers, racemic compounds, metabolites, derivatives, pharmaceutically acceptable salts, in combination with acids or bases, and the like) and methods of using these compounds as antagonists of the anti-apoptotic effects of Bcl-2 family member proteins (e.g., Bcl-2, Bcl-XL, and the like). The present invention also provides compositions comprising gossypol compounds and optionally one or more additional therapeutic agents (e.g., anticancer/chemotherapeutic agents). The present invention also provides methods for treating diseases and pathologies (e.g., neoplastic diseases) comprising administering a composition comprising gossypol compounds and optionally one or more additional therapeutic agents (e.g., anticancer/chemotherapeutic agents) and/or techniques (e.g., radiation therapies, surgical interventions, and the like) to a subject or in vitro cells, tissues, and organs.
摘要翻译：本发明涉及Bcl-2家族蛋白质的天然存在和化学合成的小分子拮抗剂。特别地，本发明提供了棉酚化合物（例如异构体，对映异构体，外消旋化合物，代谢物，衍生物，药学上可接受的盐，与酸或碱的组合等）和使用这些化合物作为抗 - Bcl-2家族蛋白（如Bcl-2，Bcl-XL等）的凋亡作用。本发明还提供包含棉酚化合物和任选的一种或多种另外的治疗剂（例如抗癌/化学治疗剂）的组合物。本发明还提供了治疗疾病和病症（例如，肿瘤疾病）的方法，包括施用包含棉酚化合物和任选的一种或多种另外的治疗剂（例如抗癌/化学治疗剂）和/或技术（例如，放射疗法，外科手术等）到受试者或体外细胞，组织和器官。

8. 发明申请

US20090118377A1 APOGOSSYPOLONE AND THE USES THEREOF 审中-公开
标题翻译： APOGOSSYPOLONE及其用途
公开(公告)号：US20090118377A1
公开(公告)日：2009-05-07
申请号：US12352399
申请日：2009-01-12
申请人： Shaomeng Wang , Jianyong Chen , Zaneta Nikolovska-Coleska , Dajun Yang
发明人： Shaomeng Wang , Jianyong Chen , Zaneta Nikolovska-Coleska , Dajun Yang
IPC分类号： A61K31/122 , C12N5/00 , A61P35/00
CPC分类号： C07C50/30 , A45C11/00 , A45C11/04 , A45C13/42 , C07C39/14 , C07C46/00 , C07C50/32 , C07C67/08 , C07C67/29 , C07C69/017 , C07C69/21
摘要： The invention relates to the compound apogossypolone and salts and prodrugs thereof. Apogossypolone functions as an inhibitor of Bcl-2 family proteins. The invention also relates to the use of apogossypolone for inhibiting hyperproliferative cell growth, for inducing apoptosis in cells and for sensitizing cells to the induction of apoptotic cell death.
摘要翻译：本发明涉及化合物果糖酚及其盐和前药。聚鸟苷酸作为Bcl-2家族蛋白的抑制剂起作用。本发明还涉及用于抑制过度增殖细胞生长，用于诱导细胞凋亡和促进细胞诱导凋亡细胞死亡的用途。

9. 发明申请

US20090010878A1 Pulsatile dosing of gossypol for treatment of disease 审中-公开
标题翻译：棉酚的脉冲给药用于治疗疾病
公开(公告)号：US20090010878A1
公开(公告)日：2009-01-08
申请号：US12155327
申请日：2008-06-02
申请人： Jon T. Holmlund , Mel Sorensen , Lance Leopold , Dajun Yang
发明人： Jon T. Holmlund , Mel Sorensen , Lance Leopold , Dajun Yang
IPC分类号： A61K31/11 , A61K38/20 , A61P35/00
CPC分类号： A61K31/11 , A61K31/337 , A61K45/06 , Y02A50/411 , A61K2300/00
摘要： This invention relates to pulsatile dose administration of gossypol or pharmaceutical compositions thereof for treating diseases, disorders and conditions responsive to gossypol, inhibiting the activity of anti-apoptotic Bcl-2 family proteins, inducing apoptosis in cells and increasing the sensitivity of cells to inducers of apoptosis.
摘要翻译：本发明涉及棉酚的脉动剂量给药或其药物组合物，用于治疗对棉酚有反应的疾病，病症和病症，抑制抗凋亡Bcl-2家族蛋白的活性，诱导细胞凋亡，并增加细胞对诱导剂的敏感性凋亡。

10. 发明授权

US07354928B2 Small molecule inhibitors targeted at Bcl-2 有权
标题翻译：针对Bcl-2的小分子抑制剂
公开(公告)号：US07354928B2
公开(公告)日：2008-04-08
申请号：US10286085
申请日：2002-11-01
申请人： Shaomeng Wang , Dajun Yang , Istvan J. Enyedy
发明人： Shaomeng Wang , Dajun Yang , Istvan J. Enyedy
IPC分类号： A61K31/44 , A61K31/335 , A61K31/135 , A61K31/505 , A61K31/65
CPC分类号： A61K45/06 , A61K31/00 , A61K31/122 , A61K31/395 , A61K31/404 , A61K31/4184 , A61K31/444 , A61K31/452 , A61K31/473 , A61K31/4745 , A61K31/519 , A61K31/655 , A61K2300/00
摘要： The present invention relates to small molecule antagonists of Bcl-2 family proteins such as Bcl-2 and/or Bcl-XL. In particular, the present invention provides non-peptide cell permeable small molecules (e.g., tricyclo-dibenzo-diazocine-dioxides) that bind to a pocket in Bcl-2/Bcl-XL that block the anti-apoptotic function of these proteins in cancer cells and tumor tissues exhibiting Bcl-2 protein overexpression. In preferred embodiments, the small molecules of the present invention are active at the BH3 binding pocket of Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Mcl-1). The compositions and methods of the present invention are useful therapeutics for cancerous diseases either alone or in combination with chemotherapeutic or other drugs.
摘要翻译：本发明涉及Bcl-2家族蛋白质如Bcl-2和/或Bcl-X L的小分子拮抗剂。特别地，本发明提供了结合Bcl-2 / Bcl-XLL中的口袋的非肽细胞可渗透的小分子（例如三环二苯并二氮杂二恶英），其阻断抗这些蛋白在癌细胞和表达Bcl-2蛋白过表达的肿瘤组织中的凋亡功能。在优选的实施方案中，本发明的小分子在Bcl-2家族蛋白（例如Bcl-2，Bcl-X L和Mcl-1）的BH3结合口袋上是有活性的。本发明的组合物和方法单独或与化学治疗剂或其它药物组合用于癌性疾病的有用治疗剂。

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