Antitumor effects of novel highly hydrophilic and non-ATP-competitive MEK1/2 inhibitor, SMK-17
Antitumor effects of novel highly hydrophilic and non-ATP-competitive MEK1/2 inhibitor, SMK-17
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DOI：
10.1097/cad.0b013e32834c6a33
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发表时间：
2012-01-01
影响因子：
2.3
通讯作者：
Kurakata, Shinichi
中科院分区：
文献类型：
--
作者：
Kiga, Masaki;Tanzawa, Fumie;Kurakata, Shinichi
丝裂原活化蛋白激酶（MAPK）信号通路在调节肿瘤细胞增殖、存活和分化中起着重要作用。该途径的组分Ras/Raf/MEK/ERK在人类癌症中经常被激活。靶向该途径被认为是一种有前途的抗癌策略。特别是，MEK是一个有吸引力的药物靶标，因为它对ERK的高选择性。通过抑制MEK，我们可以预期有效的生长抑制和促凋亡作用。在这里，我们报告了N-[-2-（2-氯-4-碘苯胺）-3，4-二氟苯基]-甲磺酰胺的衍生物作为新的MEK 1/2抑制剂。在这些化合物中，我们发现SMK-17是具有高水溶性的有效MEK 1/2抑制剂。计算机对接研究表明，SMK-17与MEK 1的变构口袋结合。动力学研究和激酶分析仪分析证实了SMK-17的变构性质。SMK-17以非ATP竞争性方式抑制MEK 1激酶活性，对MEK 1和2具有高度选择性。SMK-17在体外对肿瘤细胞株的生长有抑制作用。特别是，似乎含有高度磷酸化的MEK 1/2和ERK 1/2的细胞系对SMK-17高度敏感。此外，与先前报道的MEK抑制剂PD 184352或U 0126不同，SMK-17不抑制ERK 5的磷酸化。在体内，SMK-17在动物模型中经口给药时表现出强效抗肿瘤活性。SMK-17选择性阻断MAPK信号通路，而不影响其他信号通路，这导致显著的抗肿瘤疗效，而没有明显的副作用。这些研究结果表明，SMK-17，一个精致的选择性，口服可利用的MEK 1/2抑制剂，是一个有用的化学生物学工具，在体外和体内表征MEK/MAPK信号转导的功能。抗癌药物23：119-130（C）2011年威科健康|利平科特威廉姆斯&威尔金斯。
The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy. In particular, MEK is an attractive drug target because of its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK. Here, we report derivatives of N-[-2-(2-chloro-4-iodophenylamino)-3,4-difluorophenyl]-methanesulfonamide as novel MEK1/2 inhibitors. Among these compounds, we found SMK-17 to be a potent MEK1/2 inhibitor with high aqueous solubility. The in-silico docking study suggested that SMK-17 is bound to an allosteric pocket of MEK1. The kinetic study and the kinase profiler analysis confirmed the allosteric nature of SMK-17. SMK-17 inhibited MEK1 kinase activity in a non-ATP-competitive manner and it was highly selective to MEK1 and 2. SMK-17 inhibited the growth of tumor cell lines in vitro. Especially, it seemed that cell lines harboring highly phosphorylated MEK1/2 and ERK1/2 were highly sensitive to SMK-17. Moreover, unlike previously reported MEK inhibitors, PD184352 or U0126, SMK-17 did not inhibit the phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models on oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways, which resulted in significant antitumor efficacy without notable side effects. These findings suggest that SMK-17, an exquisitely selective, orally available MEK1/2 inhibitor, is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling both in vitro and in vivo. Anti-Cancer Drugs 23: 119-130 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.