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. 2008 Jun;4(6):357-65.
doi: 10.1038/nchembio.90. Epub 2008 May 11.

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

Alessia Montagnoli  1 , 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
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A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Alessia Montagnoli et al. Nat Chem Biol. 2008 Jun.

Abstract

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.

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