title: A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
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.
authors.affiliation: Nerviano Medical Sciences Oncology, Via Pasteur 10, 20014 Nerviano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Montagnoli
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Valter
authors.initials: V
authors.lastname: Croci
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.forename: Sonia
authors.initials: S
authors.lastname: Rainoldi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Marchesi
authors.forename: Marcello
authors.initials: M
authors.lastname: Tibolla
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tenca
authors.forename: Deborah
authors.initials: D
authors.lastname: Brotherton
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.forename: Veronica
authors.initials: V
authors.lastname: Patton
authors.forename: Rachele
authors.initials: R
authors.lastname: Alzani
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciavolella
authors.forename: Francesco
authors.initials: F
authors.lastname: Sola
authors.forename: Antonio
authors.initials: A
authors.lastname: Molinari
authors.forename: Daniele
authors.initials: D
authors.lastname: Volpi
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Marina
authors.initials: M
authors.lastname: Cattoni
authors.forename: Sandra
authors.initials: S
authors.lastname: Healy
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.forename: Jurgen
authors.initials: J
authors.lastname: Moll
authors.forename: Aaron
authors.initials: A
authors.lastname: Bensimon
authors.forename: Ermes
authors.initials: E
authors.lastname: Vanotti
authors.forename: Corrado
authors.initials: C
authors.lastname: Santocanale
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D064111:Minichromosome Maintenance Complex Component 2; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D010766:Phosphorylation; D010881:Piperidones / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C531237:PHA 767491; D010881:Piperidones; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D054852:Small Molecule Libraries; D004247:DNA; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2