845714-00-3
PHA-767491
CAS: 845714-00-3
Molecular Formula: C12H11N3O
845714-00-3 - Names and Identifiers
845714-00-3 - Physico-chemical Properties
| 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. |
845714-00-3 - Reference
| 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. |
845714-00-3 - Preparation solution concentration reference
| 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 |
Last Update：2024-01-02 23:10:35
845714-00-3 - Cell Experiment
For assays in 96 well plates 2500 cells are plated per well. After 24 hours, cells are treated with small molecule inhibitors and incubated for 72 hours at 37°C. Subsequently the cells are lysed and the ATP content is measured as an indicator of metabolically active cells using the CellTiter-Glo assay. IC50 values are calculated using the GraphPad software. For assays in six well plates, 100,000 cells are plated per well. After 24 hours, cells are treated with small molecule inhibitors and incubated for varying time points. Cells are trypsinized and a suspension is made in 5 mL of phosphate buffered saline. 30 µL of this suspension is mixed with 30 µL of CellTiter-Glo reagent followed by a 10-minute incubation at room temperature. Luminescence is measured using EnVision 2104 Multilabel Reader and BioTek Synergy Neo Microplate Reader.
Last Update：2023-08-16 21:32:38
845714-00-3 - Reference Information
| 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. |
Last Update：2024-04-10 22:29:15
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Product Name: PHA-767491 Visit Supplier Webpage Request for quotation
CAS: 845714-00-3
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
Wechat: 18301782025
CAS: 845714-00-3
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
Wechat: 18301782025
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