PHA-767491

Uses

PHA 767491 is a potent and selective ATP-competitive dual inhibitor cdc7/cdk9. It blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Inhibits cell proliferation in a variety of human cell lines and induces apoptosis in a p53-independent manner in vivo. Also inhibits mitogen-activated protein kinase-activated protein kinase-2 (MK-2).

Uses

Cdc7 kinase is a key regulator of the S-phase of the cell cycle. It is known to promote the activity of DNA replication origins in eukaryotic organisms. Inhibition of Cdc7 kinase causes blockade of DNA synthesis in human cell lines. Tumor cells are then funneled into the apoptotic pathway in a p53-independent manner. Pharmacological inhibition of Cdc7 kinase can be an effective strategy for the development of oncologic therapeutics useful for treatment of cancers. PHA 767491 HYDROCHLORIDE is a potent inhibitor of Cdc7 kinase with an IC50 value of 10 nM in the presence of 1.5 μM ATP. At 10 μM, PHA 767491 HYDROCHLORIDE induces apoptotic cell death in multiple cancer cell types. PHA 767491 HYDROCHLORIDE also inhibits Cdk9, a kinase involved in the phosphorylation of RNA polymerase II and in transcriptional regulation of gene expression, with an IC50 value of 34 nM.[Cayman Chemical]

Definition

ChEBI: 2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one is a pyrrolopyridine.

Biological Activity

Potent, ATP-competitive dual cdc7/cdk9 inhibitor (IC 50 values are 10 and 34 nM respectively) that prevents initiation of DNA replication. Inhibits cell proliferation in a variety of human cell lines (IC 50 ~ 0.86 - 5.87 μ M) and induces apoptosis in a p53-independent manner in vivo . Also inhibits mitogen-activated protein kinase-activated protein kinase-2 (MK-2) (IC 50 = 171 nM).

in vivo

target

cdc7

IC 50

CDK9: 34 nM (IC₅₀); CDK2: 240 nM (IC₅₀); CDK1: 250 nM (IC₅₀); CDK5: 460 nM (IC₅₀); GSK3-β: 220 nM (IC₅₀); Mk2: 470 nM (IC₅₀); Plk1: 980 nM (IC₅₀); Chk2: 1100 nM (IC₅₀)