利索-全球专利检索

  1. 登录
  2. 注册

搜索结果

43 条记录 (耗时 0.029 秒)

    GAMMA-AA-PEPTIDE STAT3/DNA INHIBITORS AND METHODS OF USE
    2.
    发明申请
    GAMMA-AA-PEPTIDE STAT3/DNA INHIBITORS AND METHODS OF USE 有权

    公开(公告)号：US20170101439A1

    公开(公告)日：2017-04-13

    申请号：US15332402

    申请日：2016-10-24

    申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc.

    发明人： Said M. Sebti ,  Jianfeng Cai

    IPC分类号： C07K7/02

    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 γ-AApeptide-based one-bead-one-compound (OBOC) combinatorial library was used, and identified γ-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 γ-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”.

    Dual inhibitors of farnesyltransferase and geranylgeranyltransferase I
    4.
    发明授权
    Dual inhibitors of farnesyltransferase and geranylgeranyltransferase I 有权
    法呢基转移酶和香叶基香叶基转移酶I的双重抑制剂

    公开(公告)号：US09040563B2

    公开(公告)日：2015-05-26

    申请号：US13792900

    申请日：2013-03-11

    申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc. ,  Yale University

    发明人： Said M. Sebti ,  Andrew Hamilton

    IPC分类号： C07D233/64 ,  C07D233/84 ,  C07D401/12 ,  C07D401/14 ,  C07D403/14 ,  C07D409/14 ,  C07D413/14 ,  A61K31/095 ,  A61K31/10 ,  A61K31/4164 ,  A61K31/417 ,  A61K31/66 ,  C07D403/12

    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-I (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-I (GGTase-I). 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 Y361β 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I（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。 对于相关的异戊烯基转移酶er牛儿基基转移酶I（GGTase-I），几种抑制剂证明对hFTase具有高度选择性。 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说明，对 - 苄腈部分通过“p” - 与Y361＆bgr的堆叠相互作用 残留物，表明抑制剂组分的重要性。

    COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC
    5.
    发明申请
    COMPOUNDS AND METHODS FOR INDUCING APOPTOSIS IN CANCER CELLS USING A BH3 ALPHA-HELICAL MIMETIC 审中-公开
    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：US20130295185A1

    公开(公告)日：2013-11-07

    申请号：US13940967

    申请日：2013-07-12

    申请人： H. Lee Moffitt Cancer Center and Research Institute, Inc. ,  Intezyne Technologies, Inc. ,  Yale University

    发明人： Said M. Sebti ,  Andrew D. Hamilton ,  Kevin Sill ,  Adam Carie

    IPC分类号： C07C59/70 ,  A61K31/194 ,  A61K45/06 ,  A61K9/107

    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-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 Bcl-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BH3α-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Bcl-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。