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1. 发明申请

WO2015164870A1 GAMMA-AA-PEPTIDE STAT3/DNA INHIBITORS AND METHODS OF USE 审中-公开
标题翻译： GAMMA-AA-PEPTIDE STAT3 / DNA抑制剂及其使用方法
公开(公告)号：WO2015164870A1
公开(公告)日：2015-10-29
申请号：PCT/US2015/027801
申请日：2015-04-27
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , UNIVERSITY OF SOUTH FLORIDA , SEBTI, Said, M. , CAI, Jianfeng
发明人： SEBTI, Said, M. , CAI, Jianfeng
IPC分类号： A61K31/198
CPC分类号： C07K7/02 , C07C237/22
摘要： STAT3 hyperphosphorylation, dimerization and DNA binding are required for its ability to contribute to malignant transformation. As such, STAT3 has been recognized as a promising target for cancer therapy. Although a number of inhibitors of STAT3-STAT3 dimerization have been reported, molecular ligands that prevent interactions between STAT3 and DNA are very rare. The Υ-AApeptide-based one-bead-one-compound (OBOC) combinatorial library was used, and identified Υ-AApeptides that can selectively inhibit STAT3/DNA interaction and suppress the expression levels of STAT3 target genes in intact cells. The results not only validate Υ-AApeptides as novel inhibitors of STAT3 signaling pathway, but also demonstrate that in addition to the SH2 domain, the DNA binding domain of STAT3 is targetable for the development of new generation of anti-cancer therapeutics. This also validates the approach of OBOC combinatorial library for the identification of ligands targeting traditionally recognized "undruggable targets".
摘要翻译：需要STAT3高磷酸化，二聚化和DNA结合才能促成恶性转化。因此，STAT3已经被认为是癌症治疗的有希望的靶标。尽管已经报道了许多STAT3-STAT3二聚化抑制剂，但是阻止STAT3和DNA之间相互作用的分子配体是非常罕见的。使用基于Υ-AA肽的单珠一化合物（OBOC）组合文库，并鉴定出可以选择性抑制STAT3 / DNA相互作用并抑制完整细胞中STAT3靶基因表达水平的Υ-AA肽。结果不仅验证了Υ-AA肽作为STAT3信号通路的新型抑制剂，而且还证明除SH2结构域外，STAT3的DNA结合结构域可用于开发新一代抗癌治疗剂。这也验证了OBOC组合库用于识别针对传统认可的“不可抵赖目标”的配体的方法。

2. 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。

3. 发明申请

WO2010102286A2 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：WO2010102286A2
公开(公告)日：2010-09-10
申请号：PCT/US2010/026531
申请日：2010-03-08
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： A61K31/045 , A61K31/41 , A61K31/4196 , A61K31/38 , 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

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

WO2008070100A1 COMPOSITIONS INCLUDING TRICIRIBINE AND EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITOR COMPOUNDS OR SALTS THEREOF AND METHODS OF USE THEREOF 审中-公开
标题翻译：包含鲑鱼碱和表皮生长因子受体抑制剂化合物或其盐的组合物及其使用方法
公开(公告)号：WO2008070100A1
公开(公告)日：2008-06-12
申请号：PCT/US2007/024873
申请日：2007-12-05
申请人： UNIVERSITY OF SOUTH FLORIDA , CHENG, Jin, Q. , SEBTI, Said, M.
发明人： CHENG, Jin, Q. , SEBTI, Said, M.
IPC分类号： A61K31/517 , A61K31/7064 , A61P35/00
CPC分类号： A61K31/517 , A61K31/7064 , A61K45/06 , A61K2300/00
摘要： This application relates to combination therapies including triciribine compounds and epidermal growth factor receptor inhibitor compounds, particularly erlotinib-like compounds and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.
摘要翻译：本申请涉及联合治疗，包括三西立滨化合物和表皮生长因子受体抑制剂化合物，特别是埃罗替尼样化合物和具有降低的毒性的组合物，用于治疗和预防肿瘤，癌症和其他与细胞增殖异常。

6. 发明申请

WO2007062222A2 INHIBITION OF CELL PROLIFERATION 审中-公开
标题翻译：抑制细胞增殖
公开(公告)号：WO2007062222A2
公开(公告)日：2007-05-31
申请号：PCT/US2006/045410
申请日：2006-11-22
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： A61K31/675 , A61K31/53
CPC分类号： C07C323/45 , C07C279/06 , C07C335/32 , C07D213/53 , C07D215/12 , C07D233/30 , C07D233/84 , C07D235/28 , C07D249/12 , C07D249/14 , C07D277/40 , C07D277/42 , C07D317/56 , C07D317/58
摘要： The disclosed modulators of Rb:Raf-1 interactions are potent, selective disruptors of Rb:Raf-1 binding, with IC 50 values ranging from 80 nM to 500 nM. Further, these compounds are surprisingly effective in inhibiting a wide variety of cancer cells, including osteosarcoma, epithelial lung carcinoma, non small cell lung carcinoma, three different pancreatic cancer cell lines, two different glioblastoma cell lines, metastatic breast cancer, melanoma, and prostate cancer. Moreover, the disclosed compounds effectively disrupt angiogenesis and significantly inhibited tumors in nude mice derived from human epithelial lung carcinoma tumors. Accordingly, the disclosed compounds, pharmaceutical compositions comprising the compounds, methods of inhibiting cell proliferation, methods of treating subjects with cancer, and methods of preparing the disclosed compounds are provided.
摘要翻译：所公开的Rb：Raf-1相互作用的调节剂是Rb：Raf-1结合的有效的选择性破坏剂，80nM至500nM的IC 50 N值。此外，这些化合物令人惊奇地有效地抑制多种癌细胞，包括骨肉瘤，上皮性肺癌，非小细胞肺癌，三种不同的胰腺癌细胞系，两种不同的胶质母细胞瘤细胞系，转移性乳腺癌，黑素瘤和前列腺癌症。此外，所公开的化合物有效地破坏了血管发生，并显着抑制了源自人上皮性肺癌肿瘤的裸鼠中的肿瘤。因此，提供了所公开的化合物，包含该化合物的药物组合物，抑制细胞增殖的方法，治疗患有癌症的受试者的方法以及制备所公开的化合物的方法。

7. 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。

8. 发明申请

WO2004073650A3 PEPTIDOMIMETIC INHIBITORS OF STAT3 ACTIVITY AND THEIR MEDICAL USES 审中-公开
标题翻译： STAT3活性的肽抑制剂及其医学用途
公开(公告)号：WO2004073650A3
公开(公告)日：2004-10-21
申请号：PCT/US2004005030
申请日：2004-02-20
申请人： UNIV SOUTH FLORIDA , TURKSON JAMES , JOVE RICHARD , SEBTI SAID M , HAMILTON ANDREW D
发明人： TURKSON JAMES , JOVE RICHARD , SEBTI SAID M , HAMILTON ANDREW D
IPC分类号： A61K38/00 , A61K38/04 , A61P35/00 , C07K5/04 , C07K5/06 , C07K5/08 , C07K7/06 , A61K38/05
CPC分类号： C07K7/06 , A61K38/00 , C07K5/06191 , C07K5/0827
摘要： The subject invention concerns compositions and methods for blocking cancer cell growth or proliferation and/or inducing cancer cell death. Compositions of the present invention are peptidomimetics that inhibit STAT function. Peptidomimetics of the invention include dipeptides of the formula RY*L (where Y* represents phosphotyrosine), with the R group at the Y-1 position and L=Leu, Val, Ala or a non-polar amino acid. R is preferably aryl or heteroaryl, eventually substituted with halogens, amino and nitro groups. Peptidomimetics of the invention disrupt Stat3 activation and function. Peptidomimetics of the invention significantly inhibit tumor cell growth and induce tumor cell death.
摘要翻译：本发明涉及用于阻断癌细胞生长或增殖和/或诱导癌细胞死亡的组合物和方法。本发明的组合物是抑制STAT功能的肽模拟物。本发明的肽模拟物包括式RY * L（其中Y *表示磷酸酪氨酸）的二肽，其中R基团在Y-1位置，L = Leu，Val，Ala或非极性氨基酸。 R优选为芳基或杂芳基，最终被卤素，氨基和硝基取代。本发明的肽模拟物破坏Stat3的活化和功能。本发明的肽模拟物显着抑制肿瘤细胞生长并诱导肿瘤细胞死亡。

9. 发明申请

WO2004073650A2 PEPTIDOMIMETIC INHIBITORS OF STAT ACTIVITY AND USES THEREOF 审中-公开
标题翻译： STAT活性的肽抑制剂及其用途
公开(公告)号：WO2004073650A2
公开(公告)日：2004-09-02
申请号：PCT/US2004/005030
申请日：2004-02-20
申请人： UNIVERSITY OF SOUTH FLORIDA , TURKSON, James , JOVE, Richard , SEBTI, Said, M. , HAMILTON, Andrew, D.
发明人： TURKSON, James , JOVE, Richard , SEBTI, Said, M. , HAMILTON, Andrew, D.
IPC分类号： A61K
CPC分类号： C07K7/06 , A61K38/00 , C07K5/06191 , C07K5/0827
摘要： The subject invention concerns compositions and methods for blocking cancer cell growth or proliferation and/or inducing cancer cell death. Compositions of the present invention are peptidomimetics that inhibit STAT function. Peptidomimetics of the invention include compounds of the formula RY*L (where Y* represents phosphotyrosine), with the R group at the Y- position. Peptidomimetics of the invention disrupt Stat3 activation and function. Peptidomimetics of the invention significantly inhibit tumor cell growth and induce tumor cell death.
摘要翻译：本发明涉及用于阻断癌细胞生长或增殖和/或诱导癌细胞死亡的组合物和方法。本发明的组合物是抑制STAT功能的肽模拟物。本发明的肽模拟物包括式RY * L（其中Y *表示磷酸酪氨酸）的化合物，其中R基在Y-位。本发明的肽模拟物破坏Stat3的活化和功能。本发明的肽模拟物显着抑制肿瘤细胞生长并诱导肿瘤细胞死亡。

10. 发明申请

WO0238751A3 RAS/P21 TRANSGENIC MOUSE 审中-公开
标题翻译： RAS / P21转基因鼠
公开(公告)号：WO0238751A3
公开(公告)日：2003-08-14
申请号：PCT/US0143014
申请日：2001-11-08
申请人： UNIV SOUTH FLORIDA , SEBTI SAID M , ADNANE JALILA , PLEDGER WARREN J , JACKSON ROSALIND
发明人： SEBTI SAID M , ADNANE JALILA , PLEDGER WARREN J , JACKSON ROSALIND
IPC分类号： A01K67/027 , C07K14/82 , C12N15/85 , C12N15/00 , A61K49/00 , C12N5/10
CPC分类号： A01K67/0276 , A01K67/0275 , A01K2217/05 , A01K2217/075 , A01K2227/105 , A01K2267/0331 , C07K14/82 , C12N15/8509
摘要： A transgenic rodent that constitutively expresses a ras protein in at least one tissue, is p21 null in at least one chromosome, and exhibits enhanced and accelerated ras-dependent tumorigenesis, together with methods for using said rodent, or cells derived thereof, for screening compounds or treatments for antitumor activity. In preferred embodiments, the rodent is a transgenic mouse that expresses a human ras oncogene operably linked to human regulatory sequences, and the cells of the mouse have at least one copy of a p21 transgene, whereby the mouse constitutively expresses a ras oncogene, and has decreased expression of p21. The rodents of the invention are useful in the study of ras-dependent oncogenesis and in the developments of treatments thereto.
摘要翻译：在至少一个组织中组成型表达ras蛋白质的转基因啮齿类动物在至少一个染色体中p21无效，并且表现出增强和加速的ras依赖性肿瘤发生，以及使用所述啮齿动物或其衍生的细胞的筛选化合物的方法或治疗抗肿瘤活性。在优选的实施方案中，啮齿动物是表达与人调节序列可操作地连接的人ras致癌基因的转基因小鼠，并且小鼠的细胞具有p21 转基因的至少一个拷贝，由此鼠组成型地表达 ras致癌基因，并降低p21的表达。本发明的啮齿动物可用于研究ras依赖性肿瘤发生和其治疗发展。

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