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Montagnoli, A,Valsasina, B,Croci, V,Menichincheri, M,Rainoldi, S,Marchesi, V,Tibolla, M,Tenca, P,Brotherton, D,Albanese, C,Patton, V,Alzani, R,Ciavolella, A,Sola, F,Molinari, A,Volpi, D,Avanzi, N,Fiorentini, F,Cattoni, M,Healy, S,Ballinari, D,Pesenti, E,Isacchi, A,Moll, J,Bensimon, A,Vanotti, E,Santocanale, C
2008
June
Nature Chemical Biology
A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity
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Optional Fields
HUMAN CDC7-RELATED KINASE IN-VITRO PHOSPHORYLATION HUMAN CANCER-CELLS S-PHASE HUMAN HOMOLOG PROTEIN YEAST APOPTOSIS AGENTS CYCLE
4
357
365
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.
DOI 10.1038/nchembio.90
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