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1. 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.

2. 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。

3. 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。

4. 发明申请

WO2012034038A2 DUAL INHIBITORS OF FARNESYLTRANSFERASE AND GERANYLGERANYLTRANSFERASE I 审中-公开
标题翻译： FARNESYLTRANSFERASE和GERANYLGERANYLTRANSFERASE的双重抑制剂I
公开(公告)号：WO2012034038A2
公开(公告)日：2012-03-15
申请号：PCT/US2011/051034
申请日：2011-09-09
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , YALE UNIVERSITY , SEBTI, Said, M. , HAMILTON, Andrew
发明人： SEBTI, Said, M. , HAMILTON, Andrew
IPC分类号： A61K31/4164 , A61K31/417 , A61K31/095 , A61K31/10 , 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 IC 50 value of 25 nM and a whole cell H-Ras processing IC 50 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 π-π stacking interaction with the Y361 β residue, suggesting an importance of this component of the inhibitors.
摘要翻译：许多GTP酶如Ras，Ral和Rho需要翻译后法尼烯化或香叶基香叶基化以介导恶性转化。基于乙二胺支架，开发了双重法尼基转移酶（FT）（FTI）和香叶基香叶基转移酶-1（GGT-1）抑制剂（GGTI）作为抗癌剂。在4倍取代的乙二胺支架的基础上，抑制剂结构简单且易于衍生化，促进广泛的结构 - 活性关系研究。最有效的抑制剂是化合物表现出25nM的体外抑制IC50值和全细胞H-Ras处理IC50值 90 nM。几种抑制剂证明hFTase对相关的异戊烯基转移酶ge牛儿基ge牛儿基转移酶-1（GGTase-1）具有高度选择性。在大鼠FTase的活性位点中与焦磷酸法尼基共结晶的抑制剂的晶体结构说明，对 - 苯甲腈部分通过与Y361β残基的π-π堆积相互作用而稳定，这表明该抑制剂的该组分的重要性。 / p>

5. 发明申请

WO2007117699A3 INHIBITION OF SHP2/PTPN11 PROTEIN TYROSINE PHOSPHATASE BY NSC-87877, NSC-117199 AND THEIR ANALOGS 审中-公开
公开(公告)号：WO2007117699A3
公开(公告)日：2007-10-18
申请号：PCT/US2007/008876
申请日：2007-04-09
申请人： UNIVERSITY OF SOUTH FLORIDA , H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , 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： A01N43/00 , A61K31/33
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.

6. 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。

7. 发明申请

WO2012135697A2 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：WO2012135697A2
公开(公告)日：2012-10-04
申请号：PCT/US2012/031575
申请日：2012-03-30
申请人： H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE INC. , 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 , C07D403/04 , A61K31/506 , A61P35/00
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。

8. 发明申请

WO2021102038A1 AKT INHIBITORS FOR ENHANCING CHIMERIC T CELL PERSISTENCE 审中-公开
公开(公告)号：WO2021102038A1
公开(公告)日：2021-05-27
申请号：PCT/US2020/061107
申请日：2020-11-18
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE INC.
发明人： DAVILA, Marco, L. , SEBTI, Said, M.
IPC分类号： A61K35/14 , A61K35/17 , A61K38/00 , A61K39/395
摘要： Relapse in adoptive cell transfer of CAR-T cells is often the result of CAR-T cells disappearance. Disclosed herein a method for enhancing CAR-T cell therapy in a subject, comprising administering to a subject undergoing adoptive cell transfer of therapeutic CAR-T cells an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells. As a consequence, a subject treated with a combination of CAR-T cells and an Akt inhibitor is less likely to relapse. Therefore, also disclosed herein is a method for treating a subject, comprising adoptively transfering to the subject an effective amount of a composition comprising a CAR-T cell, and administering to the subject an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells.

9. 发明申请

WO2018226791A1 GERANYLGERANYLTRANSFERASE I INHIBITOR FOR TREATMENT OF A PTEN DEFECTIVE CANCER 审中-公开
公开(公告)号：WO2018226791A1
公开(公告)日：2018-12-13
申请号：PCT/US2018/036206
申请日：2018-06-06
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC. , NEW YORK UNIVERSITY
发明人： SEBTI, Said, M. , PAGANO, Michele , KUCHAY, Shafi
IPC分类号： A61K31/495 , C12N5/09
CPC分类号： A61K31/496 , A61K45/06 , C12N5/0693 , C12N2501/72 , C12N2510/00
摘要： A method is disclosed for treating a cancer in a subject that involves administering to the subject a therapeutically affective amount of a geranylgeranyltransferase I (GGTase I) inhibitor, such as GGTI-2418, wherein the cancer comprises a defective PTEN, a hyperactivated FBXL2, or a low level of IP3R3. In some embodiments, the method further involves administering to the subject a therapeutically affective amount of an Akt inhibitor.

10. 发明申请

WO2014070859A1 STAT3 DIMERIZATION INHIBITORS 审中-公开
标题翻译： STAT3二维抑制剂
公开(公告)号：WO2014070859A1
公开(公告)日：2014-05-08
申请号：PCT/US2013/067450
申请日：2013-10-30
申请人： H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.
发明人： SEBTI, Said, M. , LAWRENCE, Nicholas, James , LAWRENCE, Harshani, Rithma
IPC分类号： C07F9/44 , C07F9/38 , A61K31/66 , A61P35/00
CPC分类号： C07F9/3834 , A61K31/192 , C07C233/76 , C07C311/18 , C07D211/10 , C07D213/16 , C07F9/3882 , C07F9/4021 , C07F9/4056
摘要： The subject matter disclosed herein relates to compositions and methods of making and using the compositions. In a further aspect, the subject matter disclosed herein relates to inhibitors of STAT3 dimerization. Methods of making these compositions as well as compositions comprising these compositions are also disclosed. Also disclosed are methods of treating or preventing certain cancers by administering to an individual in need thereof and effective amount of the compounds disclosed herein. Still further, disclosed herein are methods of inhibiting STAT3 by contacting a cell with a compound or composition as disclosed herein.
摘要翻译：本文公开的主题涉及制备和使用组合物的组合物和方法。在另一方面，本文公开的主题涉及STAT3二聚化的抑制剂。还公开了制备这些组合物的方法以及包含这些组合物的组合物。还公开了通过给予有需要的个体和有效量的本文公开的化合物来治疗或预防某些癌症的方法。此外，本文公开的是通过使细胞与本文公开的化合物或组合物接触来抑制STAT3的方法。

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