Compound Stops DNA Replication Before It Starts

Many anticancer agents interfere with the polymerization step of DNA replication, but these drugs can be toxic to noncancerous cells. Italian researchers have now found a small-molecule kinase inhibitor that stops DNA replication before it starts and could represent a new strategy for developing anticancer drugs. Screening approximately 450,000 compounds, Corrado Santocanale and coworkers at the pharmaceutical company Nerviano Medical Sciences, in Italy, identified a compound that inhibits Cdc7 kinase, an enzyme that phosphorylates proteins that unwind DNA at the replication origin (Nat. Chem. Biol., DOI: 10.1038/nchembio.90). This unwinding provides access to DNA polymerases. Unlike other DNA synthesis inhibitors, PHA-767491 neither impedes progression of the replication machinery nor sets off a sustained DNA damage response. The compound triggered apoptosis in multiple types of human cancer cells, including ones that were able to withstand other anticancer agents, but it did not kill normal fibroblast cells. The compound delayed tumor growth in several mouse cancer models.