Development of specific inhibitors against MAP kinase pathways

开发针对 MAP 激酶途径的特异性抑制剂

基本信息

  • 批准号:
    11557185
  • 负责人:
  • 金额:
    $ 8.7万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    1999
  • 资助国家:
    日本
  • 起止时间:
    1999 至 2001
  • 项目状态:
    已结题

项目摘要

(1) Blockade of the ERK-MAP kinase pathway bytreatment with PD98059, a specific inhibitor of MEK, completely suppressed the growth of tumor cells in which the pathway is constitutively activated. Selective up-regulation of P27^<Klp1> was observed alter PD98059 treatment of these tumorcells. The up-regulation of p27^<Klp1> correlated with increased association of p27^<Klp1> with cyclin E-CDK2 complexes, a concomitant inhibition of cyclin E-CDK2 kinase activity, and consequent decrease in the phosphorylation state of RB, which would culminate in the marked G1 cell cycle arrest observed in these tumor cells. Furthermore, PD98059-treatment induced a modest apoptotic response in several tumor cells in which the ERK-MAP pathway is constitutively activated. In cotrast, although PD98059 inhibited the proliferation of human diploid fibroblasts to a considerable degree, it never caused any apoptotic response in these cells. Moreover, growth-inhibited diploid fibroblasts reinitiated proliferation … More soon after removal of the inhibitor. These results strongly suggest that the the ERK-MAP kinase pathway is a potential therapeutic target in a group of tumor cells in which the pathway is constitutively activated.(2) Several polyphenols isolated from green tea leaves potently inhibited the ERK-MAP kinase pathway. These were (-)-epigallocatechin-3-gallate (EGCG) and its derivates. The molecular target of these polyphenols was suggested not to be MEK. Furthermore, several thiofravone derivativates of PD98059 such as 2-(2-amino-3-methoxyphenyl) thiochromone and 2-(2-amino-3-chrophenyl) thiochromone inhibited MEk activity more strongly than PD98059 in in vitro and in vivo experiments.(3) An anthrapyrazolone derivative (SP600125), which was originally developed as a potent inhibitor against c-Jun N-terminal kinase, was synthesized. This compound inhibited the growth of many tumor cells by arresting them at G2/M phase but not at G1 phase of the cell cycle. Thus, this compound issuggested to provide us with anew type of anti-tumor agent. Less
(1)用MEK的特异性抑制剂PD 98059阻断ERK-MAP激酶通路,可完全抑制该通路被组成性激活的肿瘤细胞的生长。在<Klp1>PD 98059处理这些肿瘤细胞后,观察到P27 α的选择性上调。p27 β的上调<Klp1>与p27 β与细胞<Klp1>周期蛋白E-CDK 2复合物的结合增加、细胞周期蛋白E-CDK 2激酶活性的伴随抑制以及RB磷酸化状态的随之降低相关,这将导致在这些肿瘤细胞中观察到的显著的G1细胞周期停滞。此外,PD 98059处理诱导了几种肿瘤细胞中的适度凋亡反应,其中ERK-MAP途径被组成性激活。相反,尽管PD 98059在相当程度上抑制人二倍体成纤维细胞的增殖,但它从未在这些细胞中引起任何凋亡反应。此外,生长抑制的二倍体成纤维细胞重新启动增殖 ...更多信息 在去除抑制剂后不久。这些结果有力地表明,ERK-MAP激酶途径是一组肿瘤细胞中的潜在治疗靶点,其中该途径被组成性激活。(2)从绿色茶叶中分离的几种多酚类物质有效地抑制了ERK-MAP激酶途径。这些是(-)-表没食子儿茶素-3-没食子酸酯(EGCG)及其衍生物。这些多酚的分子靶标被认为不是MEK。此外,在体外和体内实验中,PD 98059的几种噻呋酮衍生物如2-(2-氨基-3-甲氧基苯基)硫色酮和2-(2-氨基-3-色苯基)硫色酮比PD 98059更强烈地抑制MEk活性。(3)合成了一种蒽吡唑啉酮衍生物(SP 600125),其最初被开发为针对c-Jun N-末端激酶的有效抑制剂。该化合物通过将许多肿瘤细胞阻滞在细胞周期的G2/M期而不是G1期来抑制肿瘤细胞的生长。因此,该化合物有望为我们提供一种新型的抗肿瘤药物。少

项目成果

期刊论文数量(49)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
星野理香: "ヒト癌細胞におけるMAPキナーゼ系の異常とその制御"生化学. 72巻(印刷中). (2000)
Rika Hoshino:“MAP 激酶系统的异常及其在人类癌细胞中的调节”《生物化学》第 72 卷(出版中)。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Hoshino,R.: "Blockade of the extracellular siganl-regulated kinase pathway induces marked G1 cell cycle arrest and apootosis in tumor cells in which the pathway is constitutively activated : Up-regulation of p27^<Kip1>"J.Biol.Chem.. 276(4). 2686-2692 (200
Hoshino,R.:“阻断细胞外信号调节激酶途径可诱导显着的 G1 细胞周期停滞和肿瘤细胞的凋亡,其中该途径被组成型激活:p27^<Kip1> 的上调”J.Biol.Chem。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Ozaki, K.: "ERK pathway positively regulates the expression of Sprouty genes"Biochem. Biophys. Res. Commun.. 285(5). 1084-1088 (2001)
Ozaki, K.:“ERK 途径正向调节 Sprouty 基因的表达”Biochem。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Hoshino, R.: "Blockade of the extracellular siganl-regulated kinase pathway induces marked G1 cell cycle arrest and apopiosis in tumor cells in which the pathway is constitutively activated : Up-regulation of p27^<kip1>"J.Biol.Chem.. 276. 2686-2692 (2001)
Hoshino, R.:“阻断细胞外信号调节激酶途径可诱导肿瘤细胞显着的 G1 细胞周期停滞和凋亡,其中该途径被组成性激活:p27^<kip1> 的上调”J.Biol.Chem。
  • DOI:
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  • 影响因子:
    0
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KOHNO Michiaki其他文献

KOHNO Michiaki的其他文献

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{{ truncateString('KOHNO Michiaki', 18)}}的其他基金

Targeting the ERK-MAP kinase pathway in cancer therapy
癌症治疗中靶向 ERK-MAP 激酶通路
  • 批准号:
    22300340
  • 财政年份:
    2010
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Targeting the ERK-MAP kinase pathway in cancer therapy
癌症治疗中靶向 ERK-MAP 激酶通路
  • 批准号:
    17016056
  • 财政年份:
    2005
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
Role of MAP kinase cascades in the regulation of diverse cellular functions
MAP 激酶级联在调节多种细胞功能中的作用
  • 批准号:
    17390020
  • 财政年份:
    2005
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Role of MAP Kinase Cascade in the Regulation of Diverse Cellular Functions
MAP 激酶级联在多种细胞功能调节中的作用
  • 批准号:
    14370747
  • 财政年份:
    2002
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Role of MAP Kinase Cascade in the Regulation of Diverse Cellular Fuctions.
MAP 激酶级联在多种细胞功能调节中的作用。
  • 批准号:
    10470485
  • 财政年份:
    1998
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
Role of the ERK MAP Kinase Cascade in the Regulation of Cell Proliferation and Differentiation.
ERK MAP 激酶级联在细胞增殖和分化调节中的作用。
  • 批准号:
    08457613
  • 财政年份:
    1996
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of anti-skin ulcer drug based on the new concept -Application of the stimulatory effect of TNF-alpha on the production of NGF in fibroblasts
基于新概念的抗皮肤溃疡药物的开发-TNF-α刺激成纤维细胞产生NGF的作用的应用
  • 批准号:
    07557378
  • 财政年份:
    1995
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Regulation of mitogenic signaling pathways which involve the function of GTP-binding protein-Possible involvement of protein tyrosine phosphorylation.
涉及 GTP 结合蛋白功能的促有丝分裂信号通路的调节 - 可能涉及蛋白酪氨酸磷酸化。
  • 批准号:
    02808035
  • 财政年份:
    1990
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

相似海外基金

Identification of downstream factors of the ERK-MAP kinase pathway as a putative target for treatment of signal transduction disorders.
鉴定 ERK-MAP 激酶通路的下游因子作为治疗信号转导障碍的假定靶点。
  • 批准号:
    18K06694
  • 财政年份:
    2018
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural insight into the ERK MAP kinase signalling cascade
ERK MAP 激酶信号级联的结构洞察
  • 批准号:
    255039
  • 财政年份:
    2012
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Studentship Programs
Targeting the ERK-MAP kinase pathway in cancer therapy
癌症治疗中靶向 ERK-MAP 激酶通路
  • 批准号:
    22300340
  • 财政年份:
    2010
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Analysis of mechanisms of ERK MAP kinase phosphorylation
ERK MAP激酶磷酸化机制分析
  • 批准号:
    21790273
  • 财政年份:
    2009
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Investigating FGF ERK MAP kinase signalling in vertebrate skeletal muscle differentiation
研究脊椎动物骨骼肌分化中的 FGF ERK MAP 激酶信号传导
  • 批准号:
    G0600757/1
  • 财政年份:
    2007
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Research Grant
Characterization of a novel substrate of ERK MAP kinase that functions during vul
ERK MAP 激酶新型底物的表征,该底物在外伤期间发挥作用
  • 批准号:
    7304243
  • 财政年份:
    2007
  • 资助金额:
    $ 8.7万
  • 项目类别:
Targeting the ERK-MAP kinase pathway in cancer therapy
癌症治疗中靶向 ERK-MAP 激酶通路
  • 批准号:
    17016056
  • 财政年份:
    2005
  • 资助金额:
    $ 8.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
CXCR4 Chemokine Receptor regulation of ERK MAP Kinase
CXCR4 趋化因子受体对 ERK MAP 激酶的调节
  • 批准号:
    6796264
  • 财政年份:
    1999
  • 资助金额:
    $ 8.7万
  • 项目类别:
CXCR4 Chemokine Receptor Regulation of ERK MAP Kinase
CXCR4 趋化因子受体对 ERK MAP 激酶的调节
  • 批准号:
    8464135
  • 财政年份:
    1999
  • 资助金额:
    $ 8.7万
  • 项目类别:
CXCR4 CHEMOKINE RECEPTOR REGULATION OF ERK MAP KINASE
CXCR4 趋化因子受体对 ERK MAP 激酶的调节
  • 批准号:
    6386570
  • 财政年份:
    1999
  • 资助金额:
    $ 8.7万
  • 项目类别:
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