Montagnoli Alessia, Valsasina Barbara, Croci Valter, Menichincheri Maria, Rainoldi Sonia, Marchesi Vanessa, Tibolla Marcello, Tenca Pierluigi, Brotherton Deborah, Albanese Clara, Patton Veronica, Alzani Rachele, Ciavolella Antonella, Sola Francesco, Molinari Antonio, Volpi Daniele, Avanzi Nilla, Fiorentini Francesco, Cattoni Marina, Healy Sandra, Ballinari Dario, Pesenti Enrico, Isacchi Antonella, Moll Jurgen, Bensimon Aaron, Vanotti Ermes, Santocanale Corrado
Nerviano Medical Sciences Oncology, Via Pasteur 10, 20014 Nerviano, Italy.
Nat Chem Biol. 2008 Jun;4(6):357-65. doi: 10.1038/nchembio.90. Epub 2008 May 11.
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.
Cdc7是一种必需激酶，通过激活复制起点来促进DNA复制。在此，我们在生化和细胞实验中对强效Cdc7抑制剂PHA-767491（1）进行了表征，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，并影响复制性DNA解旋酶在Cdc7依赖性磷酸化位点的磷酸化。与目前的DNA合成抑制剂不同，PHA-767491可阻止复制起点的激活，但不阻碍复制叉的进展，且不会引发持续的DNA损伤反应。用PHA-767491处理可导致多种癌细胞类型发生凋亡性细胞死亡，并在临床前癌症模型中抑制肿瘤生长。据我们所知，PHA-767491是第一个直接影响控制DNA复制起始而非延伸机制的分子，其活性表明抑制Cdc7激酶可能是开发抗癌治疗药物的一种新策略。
