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).
Enzyme inhibitor
This cyclin kinase-directed inhibitor (FW = 213.24 g/mol; CAS 845714-00-
3, 942425-68-5 (HCl); Solubility: 24 mg/mL DMSO; <1 mg/mL Water;
Formulation: Dissolve in DMSO, and then dilute in saline), named
systematically as 2- (pyridin-4-yl) -6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-
4 (5H) -one, targets Cdc7 and CDK9, with IC50 values of 10 nM and 34 nM,
respectively. PHA-767491 displays approximately 20-times lower
inhibition of Cdk1, Cdk2 and GSK3-β, 50-times lower for MK2 and Cdk5
and 100-times lower for PLK1 and Chk2. Cyclin Target Selectivity: Cdk1
(weak, if any), Cdk2 (weak, if any), Cdk3 (weak, if any), Cdk4 (weak, if
any), Cdk5 (weak, if any), Cdk6 (weak, if any), Cdk7 (+++), Cdk8 (weak, if
any), Cdk9 (++), Cdk10 (weak, if any).
