A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
Nat Chem Biol
; 4(6): 357-65, 2008 Jun.
Article
en En
| MEDLINE
| ID: mdl-18469809
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
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperidonas
/
Pirroles
/
ADN
/
Proteínas Serina-Treonina Quinasas
/
Proteínas de Ciclo Celular
/
Inhibidores de Proteínas Quinasas
/
Replicación del ADN
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Chem Biol
Asunto de la revista:
BIOLOGIA
/
QUIMICA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Estados Unidos