A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
Nat Chem Biol
; 4(6): 357-65, 2008 Jun.
Article
em En
| MEDLINE
| ID: mdl-18469809
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperidonas
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Pirróis
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DNA
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Proteínas Serina-Treonina Quinases
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Proteínas de Ciclo Celular
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Inibidores de Proteínas Quinases
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Replicação do DNA
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article