Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy
Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy
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DOI：
10.1158/0008-5472.can-08-2627
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Niu, Huifeng
中科院分区：
文献类型：
--
作者：
Daouti, Sherif;Wang, Huisheng;Niu, Huifeng
丝裂原活化蛋白激酶（MAPK）信号转导通路在调节肿瘤细胞生长、存活、分化和血管生成中起着重要作用。Ras/Raf/MEK/ERK信号模块的关键组分在人类癌症中经常改变。靶向该途径代表了一种有前途的抗癌策略。靶向MEK 1/2的小分子抑制剂已在临床上显示出前景;然而，最终的临床概念验证仍然难以捉摸。在这里，我们报告了一种有效的和高选择性的非ATP竞争性MEK 1/2抑制剂，R 04927350，具有新颖的化学结构和独特的作用机制。它在体外和体内选择性地阻断MAPK通路信号传导，这在广谱肿瘤模型中产生显著的抗肿瘤功效。与以前报道的MEK抑制剂相比，R 04927350不仅抑制ERK 1/2，而且抑制MEK 1/2磷酸化。在癌细胞中，磷酸化MEK 1/2的高基础水平而不是磷酸化ERK 1/2似乎与对R 04927350的更高敏感性相关。此外，R 04927350可防止MEK磷酸化的反馈增加，这在其他MEK抑制剂中已观察到。我们发现，B-Raf而不是C-Raf在反馈调节中起着关键作用。R 04927350在癌症中介导的独特MAPK信号传导阻断可能降低发生耐药性的风险。因此，R 04927350代表了MAPK通路异常激活的癌症的一种新型治疗方式。[Cancer Res 2009;69（5）：1924-32]
The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The Key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non-ATP-competitive MEK1/2 inhibitor, R04927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, R04927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to R04927350. Furthermore, R04927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by R04927350 in cancer may reduce the risk of developing drug resistance. Thus, R04927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. [Cancer Res 2009;69(5):1924-32]