PHA-767491

PHA-767491 is a potent, ATP-competitive dual cdk7/cdk9 inhibitor with IC50 of 10 and 34 nM for cdk7 and CDK9, respectively. PHA-767491 blocks the activity of mitogen-activated protein kinase-activated protein kinase-2 (MK-2) with anIC50 of 171 nM. PHA-767491 inhibits DNA synthesis and replication and influences the phosphorylation of the replicative DNA helicase at cdk7-dependent phosphorylation sites. PHA-767491 does not induce a sustained DNA damage response. PHA-767491 suppresses the proliferation of cell in a variety of human cell lines with IC50 values ranging from 0.86 to 5.87 μM. PHA-767491 induces apoptosis in a p53-independent manner in vivo. Treatment with PHA-76749 leads to apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models.