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61. 发明申请

WO2012097133A3 COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC 审中-公开
标题翻译：使用BH3 ALPHA-HELICAL MIME技术诱导癌细胞凋亡的化合物和方法
公开(公告)号：WO2012097133A3
公开(公告)日：2012-11-01
申请号：PCT/US2012021049
申请日：2012-01-12
申请人： H LEE MOFFITT CANCER CT & RES , UNIV YALE , INTEZYNE TECHNOLOGIES INC , SEBTI SAID M , HAMILTON ANDREW D , SILL KEVIN , CARIE ADAM
发明人： SEBTI SAID M , HAMILTON ANDREW D , SILL KEVIN , CARIE ADAM
IPC分类号： C07C217/22 , A61K31/165 , A61P35/00 , C07C217/18
CPC分类号： A61K9/107 , A61K31/194 , A61K31/205 , A61K31/4035 , A61K31/407 , A61K31/69 , A61K45/06 , C07C59/70 , A61K2300/00
摘要： A novel BH3 a-helical mimetic, BH3-M6, which binds to Bcl-XL and prevents its binding to fluorescently-labeled Bak-BH3 peptide in vitro with an IC50 value of 734 nM is presented herein. BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-XL, Bcl-2 and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in a cell-free system and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6-induced apoptosis is caspase- and Bax- dependent. Furthermore, human cancer cells with high Bcl-2 or Bcl-XL levels are more sensitive to BH3-M6-induced cell death, suggesting that this compound can overcome drug resistance due to Bcl-2 or BCI-XL overexpression. The pan-Bcl-2 inhibitor BH3-M6 may be encapsulated in a micelle to provide a more bioavailable therapeutic agent. Specifically, the BH3-M6 compound may be encapsulated within a micelle comprising a multiblock copolymer according to the methods described herein.
摘要翻译：本文提供了一种新颖的BH3一螺旋模拟物BH3-M6，其结合Bcl-XL并且在体外阻止其与体外荧光标记的Bak-BH3肽结合，IC50值为734nM。 BH3-M6是Pan-Bcl-2拮抗剂，其抑制Bcl-XL，Bcl-2和Mcl-1与无细胞系统中多结构域Bax或Bak或仅BH3b或Bb结合完整的人类癌细胞，释放促凋亡蛋白以诱导细胞凋亡。 BH3-M6诱导的凋亡是caspase-和Bax依赖性的。此外，具有高Bcl-2或Bcl-XL水平的人类癌细胞对BH3-M6诱导的细胞死亡更敏感，这表明该化合物可以克服由于Bcl-2或BCI-XL过表达引起的耐药性。泛-Bcl-2抑制剂BH3-M6可以包封在胶束中以提供更具生物利用度的治疗剂。具体地，根据本文所述的方法，可以将BH3-M6化合物包封在包含多嵌段共聚物的胶束内。

62. 发明申请

WO2012135641A2 AURORA KINASE INHIBITORS AND METHODS OF MAKING AND USING THEREOF 审中-公开
标题翻译： AURORA激酶抑制剂及其制备和使用方法
公开(公告)号：WO2012135641A2
公开(公告)日：2012-10-04
申请号：PCT/US2012/031494
申请日：2012-03-30
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE , SEBTI, Said M. , SCHÖNBRUNN, Ernst , LAWRENCE, Nicholas J. , LAWRENCE, Harshani R. , MARTIN, Matthew P.
发明人： SEBTI, Said M. , SCHÖNBRUNN, Ernst , LAWRENCE, Nicholas J. , LAWRENCE, Harshani R. , MARTIN, Matthew P.
IPC分类号： C07D239/32 , C07D403/12 , C07D413/12 , A61K31/506 , A61P35/00
CPC分类号： A61K31/505 , A61K31/506 , A61K31/5377 , A61K31/635 , C07D239/48 , C07D295/135 , C07D401/12 , C07D403/12 , C07D413/12 , G01N33/5011
摘要： Described herein are inhibitors of Aurora kinase and their use in the treatment of cancer. Methods of screening for selective inhibitors of Aurora kinases are also disclosed.
摘要翻译：本文描述的是Aurora激酶的抑制剂及其在治疗癌症中的用途。还公开了选择性抑制Aurora激酶的筛选方法。

63. 发明申请

WO2012097133A2 COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC 审中-公开
标题翻译：使用BH3阿尔法 - 螺旋模拟物诱导癌细胞凋亡的化合物和方法
公开(公告)号：WO2012097133A2
公开(公告)日：2012-07-19
申请号：PCT/US2012/021049
申请日：2012-01-12
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , YALE UNIVERSITY , INTEZYNE TECHNOLOGIES, INC. , SEBTI, Said M. , HAMILTON, Andrew D. , SILL, Kevin , CARIE, Adam
发明人： SEBTI, Said M. , HAMILTON, Andrew D. , SILL, Kevin , CARIE, Adam
IPC分类号： C07C217/22 , C07C217/18 , A61K31/165 , A61P35/00
CPC分类号： A61K9/107 , A61K31/194 , A61K31/205 , A61K31/4035 , A61K31/407 , A61K31/69 , A61K45/06 , C07C59/70 , A61K2300/00
摘要： A novel BH3 α-helical mimetic, BH3-M6, which binds to Bcl-X L and prevents its binding to fluorescently-labeled Bak-BH3 peptide in vitro with an IC 50 value of 734 nM is presented herein. BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X L , Bcl-2 and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in a cell-free system and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6-induced apoptosis is caspase- and Bax- dependent. Furthermore, human cancer cells with high Bcl-2 or Bcl-X L levels are more sensitive to BH3-M6-induced cell death, suggesting that this compound can overcome drug resistance due to Bcl-2 or BCI-X L overexpression. The pan-Bcl-2 inhibitor BH3-M6 may be encapsulated in a micelle to provide a more bioavailable therapeutic agent. Specifically, the BH3-M6 compound may be encapsulated within a micelle comprising a multiblock copolymer according to the methods described herein.
摘要翻译：一种新的BH3α-螺旋模拟物BH3-M6，其结合Bcl-XL并防止其与荧光标记的Bak-BH3肽体外结合本文给出了734nM的IC 50值。 BH3-M6是一种泛Bcl-2拮抗剂，其抑制Bcl-XL，Bcl-2和Mcl-1与多结构域Bax或Bak或仅BH3结合的Bim或Bad 在无细胞系统和完整的人类癌细胞中，释放促凋亡蛋白以诱导细胞凋亡。 BH3-M6诱导的细胞凋亡是半胱天冬酶和Bax依赖性的。此外，具有高Bcl-2或Bcl-XL水平的人癌细胞对BH3-M6诱导的细胞死亡更敏感，表明该化合物可以克服由于Bcl-2或BCI引起的药物抗性 -X _{L 过表达。 pan-Bcl-2抑制剂BH3-M6可以包封在胶束中以提供更具生物利用度的治疗剂。具体而言，根据本文所述的方法，BH3-M6化合物可以被包封在包含多嵌段共聚物的胶束内。}

64. 发明申请

WO2011130740A3 PYRIDYLTHIAZOLE-BASED UREAS AS INHIBITORS OF RHO ASSOCIATED PROTEIN KINASE (ROCK) AND METHODS OF USE 审中-公开
公开(公告)号：WO2011130740A3
公开(公告)日：2011-10-20
申请号：PCT/US2011/032893
申请日：2011-04-18
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , LAWRENCE, Nicholas, J. , PIREDDU, Roberta , SEBTI, Said, M.
发明人： LAWRENCE, Nicholas, J. , PIREDDU, Roberta , SEBTI, Said, M.
IPC分类号： C07D417/04 , C07D417/14 , A61K31/4436 , A61K31/4439 , A61P9/00 , A61P29/00
摘要： Compounds and compositions having activity as inhibitors of Rho-associated proteinkinases (ROCKs), and methods of making and using the subject compounds are disclosed.

65. 发明申请

WO2010088457A3 METHODS FOR INDUCING TUMOR REGRESSION, INHIBITING TUMOR GROWTH, AND INDUCING APOPTOSIS IN BREAST TUMORS WITH GERANYLGERANYLTRANSFERASE I INHIBITORS 审中-公开
标题翻译：用GERANYLGERANYLTRANSFERASE I抑制剂诱导肿瘤回缩，抑制肿瘤生长和诱导乳腺肿瘤细胞凋亡的方法
公开(公告)号：WO2010088457A3
公开(公告)日：2010-09-30
申请号：PCT/US2010022498
申请日：2010-01-29
申请人： H LEE MOFFITT CANCER AND RES I , UNIV YALE , SEBTI SAID M , HAMILTON ANDREW D
发明人： SEBTI SAID M , HAMILTON ANDREW D
IPC分类号： A61K31/4965
CPC分类号： A61K31/496
摘要： Methods of inducing tumor regression, inhibiting tumor growth, and inducing apoptosis with selective peptidomimetic inhibitors of geranylgeranyltransferase I (GGTase I), are provided. In one aspect, GGTI-2418 and its methylester GGTI-2417, increase levels of the cyclin-dependent kinase (Cdk) inhibitor p27Kipl and induce breast tumor regression in vivo. In another aspect, GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27?ipl at Thrl87 and accumulates p27Kipl in the nucleus.
摘要翻译：提供了诱导肿瘤消退，抑制肿瘤生长以及使用香叶基香叶基转移酶I（GGTase I）的选择性肽模拟物抑制剂诱导凋亡的方法。一方面，GGTI-2418及其甲基酯GGTI-2417增加细胞周期蛋白依赖性激酶（Cdk）抑制剂p27Kip1的水平并诱导体内乳腺肿瘤消退。在另一方面，GGTI-2417在Thr187处抑制Cdk2介导的p27βipl的磷酸化并在细胞核中积聚p27Kip1。

66. 发明申请

WO2010005534A3 PROTEASOME INHIBITORS FOR SELECTIVELY INDUCING APOPTOSIS IN CANCER CELLS 审中-公开
标题翻译：用于选择性诱导癌细胞凋亡的抑制剂
公开(公告)号：WO2010005534A3
公开(公告)日：2010-04-08
申请号：PCT/US2009003926
申请日：2009-06-30
申请人： H LEE MOFFITT CANCER CT AND RE , UNIV SOUTH FLORIDA , LAWRENCE HARSHANI , GE YIYU , SEBTI SAID M , GUIDA WAYNE
发明人： LAWRENCE HARSHANI , GE YIYU , SEBTI SAID M , GUIDA WAYNE
IPC分类号： A61K31/38 , A61K31/192 , A61K31/255 , A61P35/00
CPC分类号： C07C323/52 , C07C311/20 , C07C311/43 , C07C323/62 , C07C2602/10 , C07D213/76 , C07D231/42 , C07D239/69 , C07D261/16 , C07D277/52 , C07D285/135 , C07D333/34 , C07D409/12
摘要： The subject invention concerns compounds having activity as inhibitors of proteasomes and methods of using the subject compounds. In one embodiment, a compound of the invention has the chemical structure shown in Formula (I), wherein R1 is an organic cyclic ring structure bonded to a sulfonamide structure; R2 is H, halogen, alkyl, -NR6R7, or heteroalkyl; R3 is H, halogen, -OH, -O-alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO2, -NH2 or substituted amines; R4 is H, alkyl, heteroalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of -NO2, alkyl, heteroalkyl, aryl, or heteroaryl, or halogen; R5 is H, -OH, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-alkyl, -O- aryl, heteroalkyl, -NO2, -NH2, or substituted amine; and R6 and R7 are independently H, O, alkyl, aryl, heterocycloalkyl, or heteroaryl, or together can form a heterocycloalkyl or a heteroaryl, any of which can be optionally substituted with one or more of -NO2, alkyl, heteroalkyl, aryl, or halogen; or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment, a compound of the invention has the chemical structure shown in Formula (II), wherein Q, W, X, Y, Z are each independently carbon, oxygen, or nitrogen; R1 is H, or X1R8; R2 is heteroalkyl, which can be optionally substituted with one or more of -OH, halogen, -C(O)OR4, alkyl, heteroalkyl, heterocycloalkyl, or heteroaryl; R3 is heterocycloalkyl, aryl, heteroaryl, any of which can be optionally substituted with one or more of a halogen or -OH; and R4 is H or alkyl; R5 is halogen, alkyl or nitro; R6 is nitro, X2R9 or a halogen; R7 is H or alkyl; R8 is H, alkyl, aryl, CH2-alkyl-aryl, -alkyl-C(O)OH, or alkyl-tetrazole (aromatic and aliphatic heterocyclic groups); R9 is H or alkyl; X1 is oxygen, nitrogen, or sulfur; X2 is oxygen, nitrogen, or sulfur; or a pharmaceutically acceptable salt or hydrate thereof.
摘要翻译：本发明涉及具有作为蛋白酶体抑制剂的活性的化合物和使用本发明化合物的方法。在一个实施方案中，本发明的化合物具有式（I）所示的化学结构，其中R 1是与磺酰胺结构键合的有机环状结构; R2是H，卤素，烷基，-NR6R7或杂烷基; R 3是H，卤素，-OH，-O-烷基，烷基，环烷基，杂环烷基，芳基，杂芳基，-NO 2，-NH 2或取代的胺; R4是H，烷基，杂烷基，芳基或杂芳基，其中任何一个可以任选被一个或多个-NO 2，烷基，杂烷基，芳基或杂芳基或卤素取代; R5是H，-OH，卤素，烷基，芳基，杂芳基，环烷基，杂环烷基，-O-烷基，-O-芳基，杂烷基，-NO2，-NH2或取代的胺; 或者一起可以形成杂环烷基或杂芳基，其中任何一个可以任选被一个或多个-NO 2，烷基，杂烷基，芳基，杂芳基，杂芳基，或卤素; 或其药学上可接受的盐或水合物。在另一个实施方案中，本发明的化合物具有式（II）所示的化学结构，其中Q，W，X，Y，Z各自独立地为碳，氧或氮; R1是H或X1R8; R 2是杂烷基，其可任选被一个或多个-OH，卤素，-C（O）OR 4，烷基，杂烷基，杂环烷基或杂芳基取代; R 3是杂环烷基，芳基，杂芳基，其中任何一个可以任选被一个或多个卤素或-OH取代; R4为H或烷基; R5是卤素，烷基或硝基; R6是硝基，X2R9或卤素; R7是H或烷基; R8是H，烷基，芳基，CH2-烷基 - 芳基， - 烷基-C（O）OH或烷基 - 四唑（芳香族和脂肪族杂环基）。 R9为H或烷基; X1是氧，氮或硫; X2是氧，氮或硫; 或其药学上可接受的盐或水合物。

67. 发明申请

WO2010025448A2 INHIBITION OF CELL PROLIFERATION 审中-公开
标题翻译：抑制细胞增殖
公开(公告)号：WO2010025448A2
公开(公告)日：2010-03-04
申请号：PCT/US2009/055509
申请日：2009-08-31
申请人： UNIVERSITY OF SOUTH FLORIDA , SEBTI, Said M. , CHELLAPPAN, Srikumar , LAWRENCE, Nicholas James
发明人： SEBTI, Said M. , CHELLAPPAN, Srikumar , LAWRENCE, Nicholas James
IPC分类号： C07C335/00 , C07D317/56 , A61P31/00 , A61K31/155 , A61K31/36
CPC分类号： C07D317/56 , A61K31/155 , A61K31/36 , C07C335/32 , C07C335/38 , G01N33/5748 , G01N2500/02
摘要： Compounds of formula (I) and (II) are provided as modulators of Rb:Raf-1 interactions which are potent, selective disruptors of Rb:Raf-1 binding. Therapeutic methods of using the compounds, for example for treating or ameliorating a cell proliferation disorder such as cancer, are provided.
摘要翻译：提供式（I）和（II）的化合物作为Rb：Raf-1相互作用的调节剂，其是Rb：Raf-1结合的有效的选择性破坏剂。提供了使用化合物的治疗方法，例如用于治疗或改善细胞增殖病症如癌症。

68. 发明申请

WO2010005534A2 PROTEASOME INHIBITORS FOR SELECTIVELY INDUCING APOPTOSIS IN CANCER CELLS 审中-公开
标题翻译：蛋白酶体抑制剂选择性诱导癌细胞凋亡的研究
公开(公告)号：WO2010005534A2
公开(公告)日：2010-01-14
申请号：PCT/US2009/003926
申请日：2009-06-30
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , UNIVERSITY OF SOUTH FLORIDA , LAWRENCE, Harshani , GE, Yiyu , SEBTI, Said, M. , GUIDA, Wayne
发明人： LAWRENCE, Harshani , GE, Yiyu , SEBTI, Said, M. , GUIDA, Wayne
IPC分类号： A61K31/38 , A61P35/00 , A61K31/255 , A61K31/192
CPC分类号： C07C323/52 , C07C311/20 , C07C311/43 , C07C323/62 , C07C2602/10 , C07D213/76 , C07D231/42 , C07D239/69 , C07D261/16 , C07D277/52 , C07D285/135 , C07D333/34 , C07D409/12
摘要： The subject invention concerns compounds having activity as inhibitors of proteasomes and methods of using the subject compounds. In one embodiment, a compound of the invention has the chemical structure shown in Formula (I), wherein R 1 is an organic cyclic ring structure bonded to a sulfonamide structure; R 2 is H, halogen, alkyl, -NR 6 R 7 , or heteroalkyl; R 3 is H, halogen, -OH, -O-alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NO 2 , -NH 2 or substituted amines; R 4 is H, alkyl, heteroalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of -NO 2 , alkyl, heteroalkyl, aryl, or heteroaryl, or halogen; R 5 is H, -OH, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-alkyl, -O- aryl, heteroalkyl, -NO 2 , -NH 2 , or substituted amine; and R 6 and R 7 are independently H, O, alkyl, aryl, heterocycloalkyl, or heteroaryl, or together can form a heterocycloalkyl or a heteroaryl, any of which can be optionally substituted with one or more of -NO 2 , alkyl, heteroalkyl, aryl, or halogen; or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment, a compound of the invention has the chemical structure shown in Formula (II), wherein Q, W, X, Y, Z are each independently carbon, oxygen, or nitrogen; R 1 is H, or X 1 R 8 ; R 2 is heteroalkyl, which can be optionally substituted with one or more of -OH, halogen, -C(O)OR 4 , alkyl, heteroalkyl, heterocycloalkyl, or heteroaryl; R 3 is heterocycloalkyl, aryl, heteroaryl, any of which can be optionally substituted with one or more of a halogen or -OH; and R 4 is H or alkyl; R 5 is halogen, alkyl or nitro; R 6 is nitro, X 2 R 9 or a halogen; R 7 is H or alkyl; R 8 is H, alkyl, aryl, CH 2 -alkyl-aryl, -alkyl-C(O)OH, or alkyl-tetrazole (aromatic and aliphatic heterocyclic groups); R 9 is H or alkyl; X 1 is oxygen, nitrogen, or sulfur; X 2 is oxygen, nitrogen, or sulfur; or a pharmaceutically acceptable salt or hydrate thereof.
摘要翻译：本发明涉及具有作为蛋白酶体抑制剂活性的化合物和使用该主题化合物的方法。在一个实施方案中，本发明的化合物具有式（I）所示的化学结构，其中R 1是与磺酰胺结构键合的有机环状环结构; R 2是H，卤素，烷基，-NR 6 R 7或杂烷基; R 3是H，卤素，-OH，-O-烷基，烷基，环烷基，杂环烷基，芳基，杂芳基，-NO 2，-NH 2，或取代的胺; R 4是H，烷基，杂烷基，芳基或杂芳基，它们中的任何一个可以任选地被一个或多个-NO 2，烷基，杂烷基，芳基，或杂芳基，或卤素; R 5是H，-OH，卤素，烷基，芳基，杂芳基，环烷基，杂环烷基，-O-烷基，-O-芳基，杂烷基，-NO 2， -NH 2 2或取代的胺; 且R 6和R 7独立地为H，O，烷基，芳基，杂环烷基或杂芳基，或者可一起形成杂环烷基或杂芳基，它们中的任何一个可以是任选地被一个或多个-NO 2，烷基，杂烷基，芳基或卤素取代; 或其药学上可接受的盐或水合物。在另一个实施方案中，本发明的化合物具有式（II）所示的化学结构，其中Q，W，X，Y，Z各自独立地为碳，氧或氮; R 1为H或X 1 R 8; R 2是杂烷基，其可以任选地被一个或多个-OH，卤素，-C（O）OR 4，烷基，杂烷基，杂环烷基或杂芳基取代 ; R 3是杂环烷基，芳基，杂芳基，它们中的任何一个可以任选地被一个或多个卤素或-OH取代; 且R 4是H或烷基; R 5是卤素，烷基或硝基; R 6是硝基，X 2 R 9或卤素; R 7是H或烷基; R 8是H，烷基，芳基，CH 2 - 烷基 - 芳基， - 烷基-C（O）OH或烷基 - 四唑（芳族和脂族杂环基团） ; R 9是H或烷基; X 1是氧，氮或硫; X 2是氧，氮或硫; 或其药学上可接受的盐或水合物。

69. 发明申请

WO2009135000A2 INHIBITION OF SHP2/PTPN11 PROTEIN TYROSINE PHOSPHATASE BY NSC-117199 AND ANALOGS 审中-公开
标题翻译： NSC-117199和模拟物对SHP2 / PTPN11蛋白酪氨酸磷酸化酶的抑制作用
公开(公告)号：WO2009135000A2
公开(公告)日：2009-11-05
申请号：PCT/US2009/042305
申请日：2009-04-30
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , UNIVERSITY OF SOUTH FLORIDA , WU, Jie , LAWRENCE, Nicholas, J. , SEBTI, Said, M. , LAWRENCE, Harshani, R.
发明人： WU, Jie , LAWRENCE, Nicholas, J. , SEBTI, Said, M. , LAWRENCE, Harshani, R.
IPC分类号： A61K31/404 , A61P35/00
CPC分类号： C07D209/40
摘要： Protein tyrosine phosphatase (PTP) Shp2 is a non-receptor PTP that involved in cell signaling and regulation of cell proliferation, differentiation, and migration. Shp2 mediates activation of kinases that are involved in the pathogenesis of human carcinoma. NSC-117199 was identified as a porent inhibitor of the protein tyrosine phosphatase (PTP a ) Shp2. A focused library of analogs incorporating an isatin scaffold was designed and evaluated for inhibition of Shp2 and Shp1 PTP activities. Several compounds were identified that selectively inhibit Shp2 over Shp1 and PTP1B with low to sub-micromolar activity. Also disclosed are methods of inhibiting a protein tyrosine phosphatase in a cell and treating cancer through selective inhibition of Shp2.
摘要翻译：蛋白酪氨酸磷酸酶（PTP）Shp2是参与细胞信号传导和调节细胞增殖，分化和迁移的非受体PTP。 Shp2介导参与人类癌症发病机制的激酶活化。 NSC-117199被鉴定为蛋白酪氨酸磷酸酶（PTPa）Shp2的细胞抑制剂。设计了一个重点的掺入靛红支架的类似物库，并评估了Shp2和Shp1 PTP活性的抑制作用。鉴定出几种化合物选择性地抑制Shp1与Shp1和PTP1B的低亚微摩尔活性。还公开了抑制细胞中的蛋白质酪氨酸磷酸酶并通过选择性抑制Shp2治疗癌症的方法。

70. 发明申请

WO2008094321A3 AKT SENSITIZATION OF CANCER CELLS 审中-公开
公开(公告)号：WO2008094321A3
公开(公告)日：2008-08-07
申请号：PCT/US2007/080441
申请日：2007-10-04
申请人： UNIVERSTIY OF SOUTH FLORIDA , SEBTI, Said M. , CHENG, Jin Q.
发明人： SEBTI, Said M. , CHENG, Jin Q.
IPC分类号： A61K31/70
摘要： Most human tumors find ways to resist anticancer drug monotherapy. Akt is considered a likely peptide providing such monotherapy drug resistance. Data indicates that Akt chemoresistance is induced in a p53-dependent manner and that inhibition of Akt may be an effective means of overcoming chemoresistance in cancer cells expressing wild-type p53. Breast, ovarian, lung cancer and leukemia cells lines were treated with combinations of Akt activation inhibitor Triciribine (TCN) or Triciribine phosphate (TCNP) and chemotherapeutic drugs to determine the efficiency of combination therapy. Additionally, cells were introduced into xenograft models to determine in vivo effects of combination treatment. Combining TCN or TCNP with other anticancer drugs overcame cytotoxic or treatment resistance. Thus, TCN and TCNP are shown to broaden the spectrum of human tumors that can be effectively treated.

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