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Nature Chemical Biology 4, 357–365 (1 June 2008) | doi:10.1038/nchembio.90

A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Alessia Montagnoli , Barbara Valsasina , Valter Croci , Maria Menichincheri , Sonia Rainoldi , Vanessa Marchesi , Marcello Tibolla , Pierluigi Tenca , Deborah Brotherton , Clara Albanese , Veronica Patton , Rachele Alzani , Antonella Ciavolella , Francesco Sola , Antonio Molinari , Daniele Volpi , Nilla Avanzi , Francesco Fiorentini , Marina Cattoni , Sandra Healy , Dario Ballinari , Enrico Pesenti , Antonella Isacchi , Jurgen Moll , Aaron Bensimon , Ermes Vanotti & Corrado Santocanale

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.