PHA-767491 HCl

Description: PHA-767491 HCl (formerly known as CAY10572 HCl) is a novel potent ATP-competitive and dual CDC7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively. It 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. 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.; Cancer Cell Int. 2016 Nov 18; 16:88.

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