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1. 发明申请

WO2012135697A3 NOVEL RHO KINASE INHIBITORS AND METHODS OF USE 审中-公开
标题翻译：新型RHO激酶抑制剂及其使用方法
公开(公告)号：WO2012135697A3
公开(公告)日：2013-01-17
申请号：PCT/US2012031575
申请日：2012-03-30
申请人： H LEE MOFFITT CANCER CT & RES , LAWRENCE NICHOLAS J , SEBTI SAID M , PIREDDU ROBERTA
发明人： LAWRENCE NICHOLAS J , SEBTI SAID M , PIREDDU ROBERTA
IPC分类号： C07D239/48 , A61K31/506 , A61P35/00 , C07D403/04
CPC分类号： A61K31/52 , A61K31/505 , A61K31/506 , A61K45/06 , C07D239/48 , C07D401/04 , C07D403/04 , C07D403/12 , C07D403/14 , C07D417/12 , C07D473/34 , A61K2300/00
摘要： The subject invention concerns materials and methods for treating diseases and disorders associated with expression of Rho associated kinases (ROCKs). Examples of diseases and disorders contemplated within the scope of the invention include, but are not limited to, oncological disorders, cardiovascular diseases, CNS disorders, and inflammatory disorders. In one embodiment, a method of the invention comprises administering a therapeutically effective amount of one or more compounds of the present invention, or a composition comprising the compounds, to a person or animal in need of treatment. The subject invention also concerns compounds that inhibit ROCKs, and compositions that comprise the inhibitor compounds of the invention. Compounds contemplated within the scope of the invention include, but are not limited to, those compounds shown in Table (5).
摘要翻译：本发明涉及用于治疗与Rho相关激酶（ROCK）的表达相关的疾病和病症的材料和方法。在本发明范围内考虑的疾病和病症的实例包括但不限于肿瘤疾病，心血管疾病，中枢神经系统疾病和炎症性疾病。在一个实施方案中，本发明的方法包括将治疗有效量的一种或多种本发明化合物或包含该化合物的组合物施用于需要治疗的人或动物。本发明还涉及抑制ROCK的化合物，以及包含本发明的抑制剂化合物的组合物。涵盖在本发明范围内的化合物包括但不限于表（5）所示的那些化合物。

2. 发明申请

WO2011130740A2 PYRIDYLTHIAZOLE-BASED UREAS AS INHIBITORS OF RHO ASSOCIATED PROTEIN KINASE (ROCK) AND METHODS OF USE 审中-公开
标题翻译：作为RHO相关蛋白激酶（ROCK）的抑制剂的基于吡啶并噻唑的UREAS和使用方法
公开(公告)号：WO2011130740A2
公开(公告)日：2011-10-20
申请号：PCT/US2011032893
申请日：2011-04-18
申请人： H LEE MOFFITT CANCER CT & RES , 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 , A61K31/4436 , A61K31/4439 , A61P9/00 , A61P29/00 , C07D417/14
CPC分类号： C07D417/04 , C07D417/14
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.
摘要翻译：公开了具有作为Rho相关蛋白激酶（ROCK）的抑制剂活性的化合物和组合物，以及制备和使用本发明化合物的方法。

3. 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。

4. 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。

5. 发明申请

WO2007136858A2 SMALL MOLECULE INHIBITORS OF STAT3 WITH ANTI-TUMOR ACTIVITY 审中-公开
标题翻译： STAT3的小分子抑制剂具有抗肿瘤活性
公开(公告)号：WO2007136858A2
公开(公告)日：2007-11-29
申请号：PCT/US2007012187
申请日：2007-05-21
申请人： H LEE MOFFITT CANCER CT & RES , UNIV SOUTH FLORIDA , UNIV CENTRAL FLORIDA , TURKSON JAMES , SEBTI SAID M , GUIDA WAYNE , YIP MAN LUN , LAWRENCE NICHOLAS , LAWRENCE HARSHANI , GREEDY BENJAMIN
发明人： TURKSON JAMES , SEBTI SAID M , GUIDA WAYNE , YIP MAN LUN , LAWRENCE NICHOLAS , LAWRENCE HARSHANI , GREEDY BENJAMIN
IPC分类号： A61K35/12
CPC分类号： A61K31/196 , A61K31/00 , A61K31/18 , A61K45/06 , C07C235/84 , C07C309/73 , C07C311/19 , G01N33/5011 , G01N33/5088 , G01N33/574 , G01N33/57407 , G01N33/57484 , A61K2300/00
摘要： The present invention concerns compounds, compositions containing these compounds, and methods of using these compounds and compositions as inhibitors of Stat3 signaling, Stat3 dimerization, Stat3-DNA binding, Stat5-DNA binding, and/or aberrant cell growthin vitro
摘要翻译：本发明涉及化合物，含有这些化合物的组合物，以及使用这些化合物和组合物作为STAT3信号传导抑制剂，Stat3二聚化，Stat3-DNA结合，Stat5-DNA结合和/或体外异常细胞生长的方法

6. 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。

7. 发明申请

WO2012034038A3 DUAL INHIBITORS OF FARNESYLTRANSFERASE AND GERANYLGERANYLTRANSFERASE I 审中-公开
标题翻译：番茄红素和甘草酸二酯抑制剂I
公开(公告)号：WO2012034038A3
公开(公告)日：2012-06-21
申请号：PCT/US2011051034
申请日：2011-09-09
申请人： H LEE MOFFITT CANCER CT & RES , UNIV YALE , SEBTI SAID M , HAMILTON ANDREW
发明人： SEBTI SAID M , HAMILTON ANDREW
IPC分类号： A61K31/4164 , A61K31/095 , A61K31/10 , A61K31/417 , A61K31/66
CPC分类号： C07D233/64 , A61K31/095 , A61K31/10 , A61K31/4164 , A61K31/417 , A61K31/66 , C07D233/84 , C07D401/12 , C07D401/14 , C07D403/12 , C07D403/14 , C07D409/14 , C07D413/14
摘要： Many GTPases such as Ras, Ral and Rho require post-translational farnestylation or geranylgeranylation for mediating malignant transformation. Dual farnesyltransferase (FT) (FTI) and geranylgeranyltransferase-l (GGT-1) inhibitors (GGTI) were developed as anticancer agents from based on an ethylenediamine scaffold. On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating extensive structure-activity relationship studies. The most potent inhibitor is compound exhibited an in vitro hFTase IC50 value of 25 nM and a whole cell H-Ras processing IC50 value of 90 nM. Several of the inhibitors proved highly selective for hFTase over the related prenyltransferase enzyme geranylgeranyltransferase-l (GGTase-l). A crystal structure of an inhibitor cocrystallized with farnesyl pyrophosphate in the active site of rat FTase illustrates that the para-benzonitrile moiety is stabilized by a p-p stacking interaction with the Y361 ß residue, suggesting an importance of this component of the inhibitors.
摘要翻译：许多GTP酶如Ras，Ral和Rho需要翻译后的法宁化或香叶基香叶基化用于介导恶性转化。双重法尼基转移酶（FT）（FTI）和香叶基香叶基转移酶-1（GGT-1）抑制剂（GGTI）被开发为基于乙二胺支架的抗癌剂。在4倍取代乙二胺支架的基础上，抑制剂结构简单，容易衍生，有利于广泛的结构 - 活性关系研究。最有效的抑制剂是化合物显示25nM的体外hFTase IC 50值，并且全细胞H-Ras加工的IC50值为90nM。证实了几种抑制剂对hFTase在相关的异戊烯基转移酶er牛儿基基转移酶-1（GGTase-1）上的选择性很高。在大鼠FTase的活性位点中与法呢基焦磷酸酯共结晶的抑制剂的晶体结构表明，对 - 苄腈部分通过与Y361β残基的p-p堆叠相互作用而稳定，这表明抑制剂组分的重要性。

8. 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。

9. 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。

10. 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。

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