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：
KOHNO Michiaki
金额：
$ 8.7万
依托单位：
Nagasaki University
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

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557185/
关键词：
MAP kinase pathway ERK-MAP kinase c-Jun N-terminal kinase Specific inhibitor Anti-tumor agent Anti-inflammatory agent Molecular Target Polyphenol 特異的阻害剤 p38MAPキナーゼフラボン MAPキナーゼ MAPキナーゼキナーゼシグナル分子

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特异性抑制剂PD98059治疗阻断ERK-MAP激酶途径，完全抑制肿瘤细胞的生长，其中在PD98059之后观察到P27^<Klp1>的选择性上调。 p27^<Klp1> 的上调与 p27^<Klp1> 与这些肿瘤细胞的关联增加相关。细胞周期蛋白 E-CDK2 复合物，伴随的细胞周期蛋白 E-CDK2 激酶活性抑制，以及随之而来的 RB 磷酸化状态的降低，最终导致在这些肿瘤细胞中观察到的显着的 G1 细胞周期停滞。在 ERK-MAP 通路被组成型激活的几种肿瘤细胞中出现适度的凋亡反应。 PD98059 在相当程度上抑制了人二倍体成纤维细胞的增殖，但从未在这些细胞中引起任何凋亡反应。此外，在去除抑制剂后，生长受到抑制的二倍体成纤维细胞很快重新开始增殖。该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) 从绿茶叶中分离出的几种多酚具有有效的作用这些多酚是 (-)-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不是 MEK，例如 2-。 (2-氨基-3-甲氧基苯基)硫色酮和2-(2-氨基-3-氯苯基)在体外和体内实验中，硫代色酮对 MEk 活性的抑制作用比 PD98059 更强。(3) 合成了蒽吡唑酮衍生物 (SP600125)，该衍生物最初是作为 c-Jun N 端激酶的有效抑制剂而开发的。通过将许多肿瘤细胞的生长抑制在细胞周期的 G2/M 期而不是 G1 期，因此，该化合物为我们提供了新的途径。抗肿瘤剂种类较少。