Molecular Formula | C12H11N3O |
Molar Mass | 213.24 |
Density | 1.287 |
Solubility | Soluble in DMSO |
Storage Condition | Desiccate at RT |
Use | PHA 767491 hydrochloride is a potent and selective ATP-competitive dual inhibitor cdc7/cdk9. PHA-767491 blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. |
In vitro study | PHA-767491 20-fold selectivity for Cdk1, Cdk2 and GSK3-β,50-fold selectivity for MK2 and Cdk 5, and 100-fold selectivity for PLK1 and chk2. PHA-767491 inhibit the proliferation of a variety of human cell lines, IC50 ranges from 0.86 μm for SF-268 cells to 5.87 μm for K562 cells, and almost all cells are significantly induced to apoptosis in a p53-independent manner, whereas 5-FU or Gemcitabine acts on only a small subset of cell lines. Unlike current DNA synthesis inhibitors, 5 μm PHA-767491 blocks the initiation of DNA replication rather than the progression of replication forks due to specific inhibition of Cdc7 kinase and Mcm2 phosphorylation at cdc7-dependent Ser40 site. 3 M PHA-767491 treatment of ABT-737-resistant OCI-LY1 and SU-DHL-4 cells significantly reduced the level of up-regulated Mcl-1, probably because Cdk9 was inhibited, resulting in the recovery of sensitivity to ABT-737. A direct mitochondria-dependent pro-apoptotic effect was observed with 1 μm PHA-767491 on quiescent chronic lymphocytic leukemia (CLL) cells with an EC50 of 0.34-0.97 μm. 5 μm PHA-767491 treatment of CD154 and IL-4 stimulated proliferating CLL cells abrogated DNA synthesis by inhibiting Cdc7 rather than triggering cell death. |
In vivo study | PHA-767491 treatment twice a day for 5 days significantly inhibited the growth of HL60 xenografts in a dose-dependent manner, with 20 mg/kg and 30 mg/kg treatment, TGI was 50% and 92%, respectively, and this effect was also significant in A2780, Mx-1, and HCT-116 xenograft models and DMBA-induced breast cancer, associated with Cdc7 inhibition, the phosphorylation of Mcm2 at the cdc7-dependent Ser40 site was subsequently reduced. |
Reference Show more | 1. Sasi NK, et al. The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds. PLoS One. 2014 Nov 20;9(11):e113300.2. Li W, et al. Dual Inhibition of Cdc7 and Cdk9 by PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil. Curr Cancer Drug Targets. 2015;15(3):196-204.3. Erbayraktar Z, et al. Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness. Cancer Cell Int. 2016 Nov 18;16:88.4. Montagnoli A, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008 Jun;4(6):357-65. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 4.69 ml | 23.448 ml | 46.896 ml |
5 mM | 0.938 ml | 4.69 ml | 9.379 ml |
10 mM | 0.469 ml | 2.345 ml | 4.69 ml |
5 mM | 0.094 ml | 0.469 ml | 0.938 ml |
biological activity | PHA-767491 is a potent, ATP-competitive, dual Cdc7/CDK9 inhibitor, IC50 is 10 nM and 34 nM, respectively, which is about 20 times higher than that of CDK1/2 and GSK3-β, and 50 times higher than that of MK2 and CDK5, the selectivity was 100-fold higher than that for PLK1 and chk2. |
signature | PHA-767491 was the first inhibitor to influence the mechanism by controlling the initiation of DNA replication rather than the extension phase. |