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1. 发明申请

WO2009135000A3 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：WO2009135000A3
公开(公告)日：2010-02-18
申请号：PCT/US2009042305
申请日：2009-04-30
申请人： H LEE MOFFITT CANCER CT AND RE , UNIV 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 , C07D209/34
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 (PTPa) 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。

2. 发明申请

WO2007117699A2 INHIBITION OF SHP2/PTPN11 PROTEIN TYROSINE PHOSPHATASE BY NSC-87877, NSC-117199 AND THEIR ANALOGS 审中-公开
标题翻译： NSC-87877，NSC-117199及其类似物对SHP2 / PTPN11蛋白酪氨酸磷酸化酶的抑制作用
公开(公告)号：WO2007117699A2
公开(公告)日：2007-10-18
申请号：PCT/US2007008876
申请日：2007-04-09
申请人： UNIV SOUTH FLORIDA , H LEE MOFFITT CANCER CT AND RE , WU JIE , LAWRENCE NICHOLAS JAMES , SEBTI SAID M , LAWRENCE HARSHANI RITHMA
发明人： WU JIE , LAWRENCE NICHOLAS JAMES , SEBTI SAID M , LAWRENCE HARSHANI RITHMA
IPC分类号： A61K31/405
CPC分类号： A61K31/405 , C07D209/40
摘要： Compounds and associated methods for inhibiting a protein tyrosine phosphatase. By a combination of experimental and virtual screenings of the NCI Diversity Set chemical library, NSC-87877 and NSC-117199 have been identified as Shp2 PTP inhibitors. Significantly, NSC-87877 is active in cell-based assays and has no detectable off-target effects in the EGF-stimulated Erkl/2 activation pathway. Additionally, a number of analogs of NSC-1 17199 have been produced. These analogs exhibit enhanced protein tyrosine phosphatase inhibition and arc found to be potent and/or selectiv e inhibitors of Shp l and/or Shp2 protein tyrosine phosphatases.
摘要翻译：用于抑制蛋白质酪氨酸磷酸酶的化合物和相关方法。通过NCI多样性集化学库的实验和虚拟筛选的组合，NSC-87877和NSC-117199已被鉴定为Shp2 PTP抑制剂。显着地，NSC-87877在基于细胞的测定中是有活性的，并且在EGF刺激的Erk1 / 2激活途径中没有检测到的脱靶作用。此外，已经生产了许多NSC-17199的类似物。这些类似物表现出增强的蛋白酪氨酸磷酸酶抑制，并且发现弧是Shp1和/或Shp2蛋白酪氨酸磷酸酶的有效和/或选择性抑制剂。

3. 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。

4. 发明申请

WO2010011666A3 INDOLINE SCAFFOLD SHP-2 INHIBITORS AND CANCER TREATMENT METHOD 审中-公开
标题翻译： INDOLINE SCAFFOLD SHP-2抑制剂和癌症治疗方法
公开(公告)号：WO2010011666A3
公开(公告)日：2010-04-22
申请号：PCT/US2009051276
申请日：2009-07-21
申请人： UNIV SOUTH FLORIDA , WU JIE , LAWRENCE NICHOLAS J , SEBTI SAID M
发明人： WU JIE , LAWRENCE NICHOLAS J , SEBTI SAID M
IPC分类号： C07D403/12 , A61K31/496 , A61P35/00
CPC分类号： C07D405/06 , C07D209/08 , C07D215/36
摘要： The subject invention concerns methods and compounds for inhibiting Shp2. In one embodiment, a compound of the invention has a chemical structure as shown in formula I or II: wherein X, Y, and Z are independently N or S; R1 is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which can be optionally substituted with one or more of halogen; alkyl; heteroalkyl; -COOH; -C(R3)3, wherein R3 can independently be any of -H or halogen; or -OR4, wherein R4 can be any of H, alkyl. or heteroalkyl; R2 is alkyl, alkylcarbonyl, heteroalkylcarbonyl, aryl, arylcarbonyl, heterocycloalkylcarbonyl, cycloalkylcarbonyl, or -C(O)NR6R7, any of which can be optionally substituted with one or more of halogen; alkyl; heteroalkyl; carbonyl; -OR4, wherein R4 can be -H, alkyl, or heteroalkyl; -OH; -C(RO3)3, wherein R3 can independently be any of -H or halogen; aryl, which can be substituted with one or more of halogen or - OR4; heterocycloalkyl; or -C(O)OR5, wherein R5 can be -H or alkyl; R6 and R7 are independently -H, alkyl, heteroalkyl, aryl, or heteroaryl; and R1 is H or alkyl; or a pharmaceutically acceptable salt or hydrate thereof.
摘要翻译：本发明涉及用于抑制Shp2的方法和化合物。在一个实施方案中，本发明的化合物具有如式I或II所示的化学结构：其中X，Y和Z独立地为N或S; R 1是环烷基，杂环烷基，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卤素取代; 烷基; 杂; -COOH; -C（R 3）3，其中R 3可以独立地为-H或卤素中的任何一个; 或-OR 4，其中R 4可以是H，烷基中的任何一个。或杂烷基; R 2是烷基，烷基羰基，杂烷基羰基，芳基，芳基羰基，杂环烷基羰基，环烷基羰基或-C（O）NR 6 R 7，它们中的任何一个可以任选地被一个或多个卤素取代; 烷基; 杂; 羰; -OR 4，其中R 4可以是-H，烷基或杂烷基; -哦; -C（RO 3）3，其中R 3可以独立地为-H或卤素中的任何一个; 芳基，其可以被一个或多个卤素或-OR 4取代; 杂环; 或-C（O）OR 5，其中R 5可以是-H或烷基; R6和R7独立地为-H，烷基，杂烷基，芳基或杂芳基; 并且R1是H或烷基; 或其药学上可接受的盐或水合物。

5. 发明申请

WO2007013997A3 INHIBITION OF THE RAF/MEK/P-ERK PATHWAY FOR TREATING CANCER 审中-公开
标题翻译：用于治疗癌症的RAF / MEK / P-ERK途径的抑制
公开(公告)号：WO2007013997A3
公开(公告)日：2009-04-23
申请号：PCT/US2006028294
申请日：2006-07-21
申请人： H LEE MOFFITT CANCER CT AND RE , SEBTI SAID M
发明人： SEBTI SAID M
IPC分类号： C07K16/00 , C12N5/06 , G01N33/574
CPC分类号： A61K31/138 , G01N33/574
摘要： The invention disclosed herein provides for methods of treating cancer using inhibitors of the Raf/Mek/P-Erk 1/2 pathway. These inhibitors include B2AR agonists (such as ARA-211 (pirbuterol) and isoproterenol), adenylyl cyclase activators, cAMP analogs and Epac activators. The invention also provides methods for diagnosing cancer in an individual.
摘要翻译：本文公开的本发明提供了使用Raf / Mek / P-Erk 1/2途径的抑制剂治疗癌症的方法。这些抑制剂包括B2AR激动剂（例如ARA-211（吡布特罗）和异丙肾上腺素），腺苷酸环化酶激活剂，cAMP类似物和Epac激活剂。本发明还提供了诊断个体癌症的方法。

6. 发明申请

WO2012135641A3 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：WO2012135641A3
公开(公告)日：2012-12-27
申请号：PCT/US2012031494
申请日：2012-03-30
申请人： H LEE MOFFITT CANCER CT AND RES INST , SEBTI SAID M , SCHOENBRUNN ERNST , LAWRENCE NICHOLAS J , LAWRENCE HARSHANI R , MARTIN MATTHEW P
发明人： SEBTI SAID M , SCHOENBRUNN ERNST , LAWRENCE NICHOLAS J , LAWRENCE HARSHANI R , MARTIN MATTHEW P
IPC分类号： C07D239/32 , A61K31/506 , A61P35/00 , C07D403/12 , C07D413/12
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：本文描述了极光激酶的抑制剂及其在治疗癌症中的用途。还公开了筛选Aurora激酶的选择性抑制剂的方法。

7. 发明申请

WO2010121212A2 INDOLINE SCAFFOLD SHP-2 INHIBITORS AND METHOD OF TREATING CANCER 审中-公开
标题翻译： INDOLINE SCAFFOLD SHP-2抑制剂和治疗癌症的方法
公开(公告)号：WO2010121212A2
公开(公告)日：2010-10-21
申请号：PCT/US2010031506
申请日：2010-04-16
申请人： H LEE MOFFIT CANCER CT AND RES , UNIV SOUTH FLORIDA , WU JIE , LAWRENCE NICHOLAS JAMES , SEBTI SAID M , LAWRENCE HARSHANI RITHMA
发明人： WU JIE , LAWRENCE NICHOLAS JAMES , SEBTI SAID M , LAWRENCE HARSHANI RITHMA
CPC分类号： C07D209/34 , C07D209/12 , C07D209/40 , C07D215/36
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. A high throughput screen identified compounds that inhibit the PTP Shp2. Several compounds were identified that selectively inhibit Shp2 over Shp1 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。高通量筛选鉴定抑制PTP Shp2的化合物。鉴定了几种化合物，选择性抑制Shp2超过Shp1，具有低至亚微摩尔的活性。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。

8. 发明申请

WO2012129564A2 PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS 审中-公开
标题翻译：使用PI-1833模拟蛋白的抗氧化蛋白酶抑制剂
公开(公告)号：WO2012129564A2
公开(公告)日：2012-09-27
申请号：PCT/US2012030574
申请日：2012-03-26
申请人： H LEE MOFFITT CANCER CT & RES , LAWRENCE HARSHANI R , SEBTI SAID M , OZCAN SEVIL
发明人： LAWRENCE HARSHANI R , SEBTI SAID M , OZCAN SEVIL
IPC分类号： C07D271/06 , A61K31/4245 , A61P35/00 , C07D413/04
CPC分类号： C07D413/04 , C07D271/04 , C07D271/06
摘要： Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).
摘要翻译：在二恶唑 - 异丙酰胺核心蛋白酶体抑制剂上集中文库合成和药物化学提供强烈抑制CT-L活性的铅化合物。结构活性关系研究表明酰胺部分和两个苯环对合成改性敏感。只有A环中的对位取代对于维持有效的CT-L抑制活性是重要的。 A环的对位疏水残基和B-环上的间位吡啶基显着改善了抑制作用。间 - 吡啶基部分改善细胞渗透性。 A环的对位脂肪链的长度是关键的丙基产生最有效的抑制剂，而较短的（即乙基，甲基或氢）或更长（即丁基，丙基和己基）链显示逐渐降低的效力。引入邻位于醚部分的立体中心（即用甲基取代一个氢）在蛋白酶体CT-L活性抑制（S-对映异构体比R-对映异构体更有效35-40倍）中证明手性鉴别。

9. 发明申请

WO2010102286A3 PROTEASOME INHIBITORS HAVING CHYMOTRYPSIN-LIKE ACTIVITY 审中-公开
标题翻译：具有抗氧化活性的活性抑制剂
公开(公告)号：WO2010102286A3
公开(公告)日：2011-01-20
申请号：PCT/US2010026531
申请日：2010-03-08
申请人： H LEE MOFFITT CANCER CT & RES , 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： A61K31/045 , A61K31/38 , A61K31/41 , A61K31/4196 , A61P35/00
CPC分类号： A61K31/045 , A61K31/38 , A61K31/41 , A61K31/4196 , C07C311/07 , C07C323/52 , C07C323/62 , C07C2602/10 , C07D333/34
摘要： Disclosed herein is the use of HLM-008182, as well as its analogues formed via in-house synthesis, as a potent proteasome inhibitors. A new method was developed for HLM-008182 through a four-step protocol and the method was further optimized to a two step protocol. The synthesis in both protocols was regioselective with TiCl4. The reaction was highly efficient with microwave assisted heating and THF as solvent. The modification around the molecule HLM-008182 established primary SAR, indicating that the proteasome inhibition activity was a function of the 2-side chain.
摘要翻译：本文公开了HLM-008182及其通过内部合成形成的类似物作为有效的蛋白酶体抑制剂的用途。通过四步协议为HLM-008182开发了一种新方法，并进一步优化了两步方案。两种方案的合成都是用TiCl4进行区域选择性的。该反应在微波辅助加热和THF作为溶剂下是高效的。分子修饰HLM-008182构建了初级SAR，表明蛋白酶体抑制活性是双侧链的功能。

10. 发明申请

WO2005094322A3 EFFECTIVE TREATMENT OF TUMORS AND CANCER WITH TRICIRIBINE AND RELATED COMPOUNDS 审中-公开
标题翻译：有效治疗肿瘤和癌症与相关化合物及相关化合物
公开(公告)号：WO2005094322A3
公开(公告)日：2005-12-29
申请号：PCT/US2005010422
申请日：2005-03-29
申请人： UNIV SOUTH FLORIDA , CHENG JIN Q , SEBTI SAID M
发明人： CHENG JIN Q , SEBTI SAID M
IPC分类号： A61K31/70 , A61K31/7076 , C07H19/02
CPC分类号： C07H17/02 , A61K31/7064
摘要： The inventors have determined, contrary to the prior art and experience, how to successfully use triciribine to treat tumors and cancer by one or a combination of (i) administering triciribine only to patients which according to a diagnostic test described below, exhibit enhanced sensitivity to the drug; (ii) use of a described dosage level that minimizes the toxicity of the drug but yet still exhibits efficacy; or (iii) use of a described dosage regimen that minimizes the toxicity of the drug.
摘要翻译：发明人已经确定，与现有技术和经验相反，如何成功地使用三苯呋嗪治疗肿瘤和癌症，其中一种或其组合（i）仅根据下述诊断试验给患者施用三苯呋嗪，表现出对毒品; （ii）使用使药物的毒性最小化但仍显示功效的所述剂量水平; 或（iii）使用最小化药物的毒性的所述剂量方案。

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