Article abstract


Nature Chemical Biology 4, 357 - 365 (2008)
Published online: 11 May 2008 | doi:10.1038/nchembio.90

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

Alessia Montagnoli1, Barbara Valsasina1, Valter Croci1, Maria Menichincheri1, Sonia Rainoldi1, Vanessa Marchesi1, Marcello Tibolla1, Pierluigi Tenca4, Deborah Brotherton4, Clara Albanese1, Veronica Patton1, Rachele Alzani1, Antonella Ciavolella1, Francesco Sola1, Antonio Molinari1, Daniele Volpi1, Nilla Avanzi1, Francesco Fiorentini1, Marina Cattoni1, Sandra Healy1, Dario Ballinari1, Enrico Pesenti1, Antonella Isacchi1, Jurgen Moll1, Aaron Bensimon2, Ermes Vanotti1 & Corrado Santocanale1,3


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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  1. Nerviano Medical Sciences Oncology, Via Pasteur 10, 20014 Nerviano, Italy.
  2. Genomic Vision, Pasteur Biotop, 28 rue du Docteur Roux, 75724 Paris cedex 15, France.
  3. National Centre for Biomedical Engineering and Sciences, National University of Ireland Galway, University Road, Galway, Ireland.
  4. Present addresses: InCura via Staffolo 60, 26040 Vicomoscano (Cremona), Italy (P.T.) and Chroma Therapeutics, 93 Milton Park, Abington OX14 5RY, UK (D.B.).

Correspondence to: Corrado Santocanale1,3 e-mail: corrado.santocanale@nuigalway.ie



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