Identification of JTP-70902, a p15INK4b-inductive compound, as a novel MEK1/2 inhibitor
Identification of JTP-70902, a p15INK4b-inductive compound, as a novel MEK1/2 inhibitor
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DOI：
10.1111/j.1349-7006.2007.00604.x
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发表时间：
2007-11-01
期刊：
影响因子：
5.7
通讯作者：
Sakai, Toshiyuki
中科院分区：
文献类型：
--
作者：
Yamaguchi, Takayuki;Yoshida, Takayuki;Sakai, Toshiyuki
INK 4家族成员p16（INK 4a）和p15（INK 4 b）通过抑制细胞周期蛋白依赖性激酶（CDK）4/6来负调节细胞周期进程。p16（INK 4a）功能活性的丧失经常在肿瘤细胞中观察到，并且被认为是致癌的主要原因之一。相反，尽管与p16（INK 4a）的生化相似性，但发现p15（INK 4 b）的缺陷频率低于p16（INK 4a），这表明p15（INK 4 b）诱导剂可能对肿瘤抑制有用。在这里，我们报告了一种新的吡啶并嘧啶衍生物，JTP-70902，它在p16（INK 4a）失活的人结肠癌HT-29细胞中表现出p15（INK 4 b）诱导活性的发现。JTP-70902还诱导另一种CDK抑制剂p27（KIP 1），并下调c-Myc和cyclin D1的表达，导致G（1）细胞周期停滞。MEK 1/2通过化合物固定化亲和色谱法鉴定为JTP-70902的分子靶标，并且这通过激酶测定中JTP-70902对MEK 1/2的抑制活性进一步证实。JTP-70902在体外抑制大多数结直肠癌细胞系和一些其他癌细胞系的生长，并在HT-29异种移植模型中显示出抗肿瘤活性。然而，JTP-70902没有抑制COLO 320 DM细胞的生长;在这些细胞中，没有检测到组成性细胞外信号调节激酶磷酸化，也没有观察到p15（INK 4 b）和p27（KIP 1）诱导。此外，发现p15（INK 4 b）缺陷型小鼠胚胎成纤维细胞比野生型小鼠胚胎成纤维细胞对JTP-70902的生长抑制作用更具抗性。这些发现表明，JTP-70902通过抑制MEK 1/2恢复CDK受体介导的细胞周期控制，并发挥有效的抗肿瘤作用。
The INK4 family members p16(INK4a) and p15(INK4b) negatively regulate cell cycle progression by inhibition of cyclin-dependent kinase (CDK) 4/6. Loss of p16(INK4a) functional activity is frequently observed in tumor cells, and is thought to be one of the primary causes of carcinogenesis. In contrast, despite the biochemical similarity to p16(INK4a), the frequency of defects in p15(INK4b) was found to be lower than in p16(INK4a), suggesting that p15(INK4b)-inductive agents may be useful for tumor suppression. Here we report the discovery of a novel pyrido-pyrimidine derivative, JTP-70902, which exhibits p15(INK4b)-inducing activity in p16(INK4a)-inactivated human colon cancer HT-29 cells. JTP-70902 also induced another CDK-inhibitor, p27(KIP1), and downregulated the expression of c-Myc and cyclin D1, resulting in G(1) cell cycle arrest. MEK1/2 was identified by compound-immobilized affinity chromatography as the molecular target of JTP-70902, and this was further confirmed by the inhibitory activity of JTP-70902 against MEK1/2 in kinase assays. JTP-70902 suppressed the growth of most colorectal and some other cancer cell lines in vitro, and showed antitumor activity in an HT-29 xenograft model. However, JTP-70902 did not inhibit the growth of COLO320 DM cells; in these, constitutive extracellular signal-regulated kinase phosphorylation was not detected, and neither p15(INK4b) nor p27(KIP1) induction was observed. Moreover, p15(INK4b)-deficient mouse embryonic fibroblasts were found to be more resistant to the growth-inhibitory effect of JTP-70902 than wild-type mouse embryonic fibroblasts. These findings suggest that JTP-70902 restores CDK inhibitor-mediated cell cycle control by inhibiting MEK1/2 and exerts a potent antitumor effect.