PHA-767491

Description: PHA-767491 (formerly also called CAY10572) is a novel and potent ATP-competitive dual inhibitor of Cdc7/CDK9 with IC50 of 10 nM and 34 nM in cell-free assays, respectively. It has potential anticancer activity and displays ca.20-fold selectivity against CDK1/2 and GSK3-beta, 50-fold selectivity against MK2 and CDK5, 100-fold selectivity against PLK1 and CHK2. PHA-767491 inhibits cell proliferation in a variety of human cell lines with IC50 of 0.86 uM for SF-268 to 5.87 uM for K562, and significantly induces apoptosis in a p53-independent manner in almost all cell lines in contrast with 5-FU or gemcitabine which only works in a few of cell lines. CDC7 is an essential kinase that promotes DNA replication by activating origins of replication. PHA-767491 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.

References: Nat Chem Biol. 2008 Jun; 4(6):357-65; Blood. 2010 Apr 22; 115(16):3304-13.

Related CAS#: 845714-00-3 (free base) 942425-68-5 (HCl) 845538-12-7 (2HCl)