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- Title
A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
- Authors
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
- 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.
- Publication
Nature chemical biology, 2008, Vol 4, Issue 6, p357
- ISSN
1552-4469
- Publication type
Journal Article
- DOI
10.1038/nchembio.90