A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Alessia Montagnoli; Barbara Valsasina; Valter Croci; Maria Menichincheri; Sonia Rainoldi; Vanessa Marchesi; Marcello Tibolla; Pierluigi Tenca; Deborah Brotherton; Clara Albanese; Veronica Patton; Rachele Alzani; Antonella Ciavolella; Francesco Sola; Antonio Molinari; Daniele Volpi; Nilla Avanzi; Francesco Fiorentini; Marina Cattoni; Sandra Healy; Dario Ballinari; Enrico Pesenti; Antonella Isacchi; Jurgen Moll; Aaron Bensimon; Ermes Vanotti; Corrado Santocanale

doi:10.1038/nchembio.90

A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity

Nat Chem Biol. 2008 Jun;4(6):357-65. doi: 10.1038/nchembio.90. Epub 2008 May 11.

Affiliation

¹ Nerviano Medical Sciences Oncology, Via Pasteur 10, 20014 Nerviano, Italy.

PMID: 18469809
DOI: 10.1038/nchembio.90

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.

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / genetics
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA / biosynthesis
DNA / drug effects*
DNA Replication / drug effects*
Dose-Response Relationship, Drug
Fibroblasts / drug effects
HeLa Cells
Humans
Mice
Mice, Nude
Mice, SCID
Minichromosome Maintenance Complex Component 2
Molecular Structure
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / chemistry
Phosphorylation
Piperidones / chemistry
Piperidones / pharmacology*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / genetics
Pyrroles / chemistry
Pyrroles / pharmacology*
Rats
Small Molecule Libraries
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Cell Cycle Proteins
Nuclear Proteins
PHA 767491
Piperidones
Protein Kinase Inhibitors
Pyrroles
Small Molecule Libraries
DNA
CDC7 protein, human
Protein Serine-Threonine Kinases
MCM2 protein, human
Minichromosome Maintenance Complex Component 2

Associated data

PubChem-Substance/49684284
PubChem-Substance/49684285
PubChem-Substance/49684286
PubChem-Substance/49684287
PubChem-Substance/49684288
PubChem-Substance/49684289
PubChem-Substance/49684290
PubChem-Substance/49684291
PubChem-Substance/49684292
PubChem-Substance/49684293
PubChem-Substance/49684294
PubChem-Substance/49684295