Daouti Sherif, Wang Huisheng, Li Wen-hui, Higgins Brian, Kolinsky Kenneth, Packman Kathryn, Specian Anthony, Kong Norman, Huby Nicholas, Wen Yang, Xiang Qing, Podlaski Frank J, He Yang, Fotouhi Nader, Heimbrook David, Niu Huifeng
Discovery Oncology, Discovery Chemistry, and Roche Discovery Technologies, Hoffmann-La Roche, Inc., Nutley, New Jersey.
Cancer Res. 2009 Mar 1;69(5):1924-32. doi: 10.1158/0008-5472.CAN-08-2627. Epub 2009 Feb 24.
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, RO4927350, 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, RO4927350 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 RO4927350. Furthermore, RO4927350 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 RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation.
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核心作用。Ras/Raf/MEK/ERK信号模块的关键组分在人类癌症中经常发生改变。靶向该通路是一种有前景的抗癌策略。靶向MEK1/2的小分子抑制剂在临床上已显示出前景；然而，最终的临床概念验证仍难以实现。在此，我们报道了一种强效且高度选择性的非ATP竞争性MEK1/2抑制剂RO4927350，其具有新颖的化学结构和独特的作用机制。它在体外和体内均选择性地阻断MAPK通路信号传导，这在广泛的肿瘤模型中产生显著的抗肿瘤疗效。与先前报道的MEK抑制剂相比，RO4927350不仅抑制ERK1/2，还抑制MEK1/2磷酸化。在癌细胞中，磷酸化MEK1/2而非磷酸化ERK1/2的高基础水平似乎与对RO4927350的更高敏感性相关。此外，RO4927350可防止MEK磷酸化的反馈性增加，这在其他MEK抑制剂中已观察到。我们表明B-Raf而非C-Raf在反馈调节中起关键作用。RO4927350在癌症中介导的独特MAPK信号传导阻断可能降低产生耐药性的风险。因此，RO4927350代表了一种针对MAPK通路异常激活的癌症的新型治疗方式。
