A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity
A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity
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DOI：
10.1038/nchembio.90
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发表时间：
2008-06-01
影响因子：
14.8
通讯作者：
Santocanale, Corrado
中科院分区：
文献类型：
--
作者：
Montagnoli, Alessia;Valsasina, Barbara;Santocanale, Corrado
Cdc 7是通过激活复制起点来促进DNA复制的必需激酶。在这里，我们在生物化学和基于细胞的测定中表征了有效的Cdc 7抑制剂PHA-767491（1），并在啮齿动物中测试了其抗肿瘤活性。我们发现，该化合物阻断DNA合成，并影响Cdc 7依赖磷酸化位点的复制DNA解旋酶的磷酸化。与目前的DNA合成抑制剂不同，PHA-767491可阻止复制起点的激活，但不会阻碍复制叉的进展，也不会引发持续的DNA损伤反应。PHA-767491治疗导致多种癌细胞类型的细胞凋亡和临床前癌症模型中的肿瘤生长抑制。据我们所知，PHA-767491是第一个直接影响控制DNA复制起始而非延长机制的分子，其活性表明Cdc 7激酶抑制可能是开发抗癌疗法的新策略。
Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.