A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
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.
Montagnoli
Alessia
A
Nerviano Medical Sciences Oncology, Via Pasteur 10, 20014 Nerviano, Italy.
Valsasina
Barbara
B
Croci
Valter
V
Menichincheri
Maria
M
Rainoldi
Sonia
S
Marchesi
Vanessa
V
Tibolla
Marcello
M
Tenca
Pierluigi
P
Brotherton
Deborah
D
Albanese
Clara
C
Patton
Veronica
V
Alzani
Rachele
R
Ciavolella
Antonella
A
Sola
Francesco
F
Molinari
Antonio
A
Volpi
Daniele
D
Avanzi
Nilla
N
Fiorentini
Francesco
F
Cattoni
Marina
M
Healy
Sandra
S
Ballinari
Dario
D
Pesenti
Enrico
E
Isacchi
Antonella
A
Moll
Jurgen
J
Bensimon
Aaron
A
Vanotti
Ermes
E
Santocanale
Corrado
C
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
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