PHA-767491Cdc7/cdk9 inhibitor, potent, ATP-competitive CAS# 845714-00-3 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 845714-00-3 | SDF | Download SDF |
PubChem ID | 11715767 | Appearance | Powder |
Formula | C12H11N3O | M.Wt | 213.24 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | CAY10572 | ||
Solubility | Soluble in DMSO > 10 mM | ||
Chemical Name | 2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one | ||
SMILES | C1CNC(=O)C2=C1NC(=C2)C3=CC=NC=C3 | ||
Standard InChIKey | DKXHSOUZPMHNIZ-UHFFFAOYSA-N | ||
Standard InChI | InChI=1S/C12H11N3O/c16-12-9-7-11(8-1-4-13-5-2-8)15-10(9)3-6-14-12/h1-2,4-5,7,15H,3,6H2,(H,14,16) | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | PHA-767491 is a potent, ATP-competitive inhibitor of cdc7 and cdk9 with 10 nM and 34 nM, respectively. | |||||
Targets | cdc7 | cdk9 | ||||
IC50 | 10 nM | 34 nM |
PHA-767491 Dilution Calculator
PHA-767491 Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 4.6896 mL | 23.4478 mL | 46.8955 mL | 93.791 mL | 117.2388 mL |
5 mM | 0.9379 mL | 4.6896 mL | 9.3791 mL | 18.7582 mL | 23.4478 mL |
10 mM | 0.469 mL | 2.3448 mL | 4.6896 mL | 9.3791 mL | 11.7239 mL |
50 mM | 0.0938 mL | 0.469 mL | 0.9379 mL | 1.8758 mL | 2.3448 mL |
100 mM | 0.0469 mL | 0.2345 mL | 0.469 mL | 0.9379 mL | 1.1724 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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PHA-767491 is a small-molecule inhibitor of Cdc7 kinase with IC50 value of 10 nM [1].
In the process of DNA synthesis, Cdc7 kinase is critical to the activation of replication origins. It phosphorylates several subunits of mini chromosome maintenance proteins (MCMs), especially the Mcm2 at Ser40 and Ser53 sites, which constitute the replicative DNA helicase. Cdc7 is overexpressed in tumor cells and tumor specimens, therefore the Cdc7 inhibitors are developed as anticancer agents. As a small-molecule Cdc7 inhibitor, PHA-767491 exerted antitumor activity through a different mechanism than other drugs target DNA replication. PHA-767491 competed with ATP for binding to Cdc7 and showed an IC50 value of 10 nM in the presence of 1.5 μM ATP [1].
PHA-767491 is a selective inhibitor. It showed no inhibitory effect on 15 kinases when tested against a panel of 38 serine/theronine and tyrosine kinases. However, it inhibited cdk1, cdk2 and GSK-3β with 20-fold less potency. Besides that, PHA-767491 was found to have inhibitory effect on Cdk9 with IC50 value of 34 nM, which made it be regarded as a dual inhibitor of Cdk7/9 kinase. When treated to a panel of 61 human cell lines, PHA-767491 caused cell proliferation inhibition with an average IC50 value of 3.17μM. It killed cells both p53-positive and p53-negative. Among the exceptions, NHDF and MCF7 cells were resistant to PHA-767491. K562 cells were less sensitive to PHA-767491 [1].
In mice bearing implanted tumors derived from HL60 cell lines, administration of PHA-767491 at dose of 20 and 30 mg/kg twice a day reduced tumor volume dose-dependently. PHA-767491 administration also resulted in 50% tumor growth inhibition in xenograft models of A2780 ovary carcinoma, HCT-116 colon carcinoma or Mx-1 mammary adenocarcinoma [1].
Reference:
[1] Montagnoli A, Valsasina B, Croci V, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nature chemical biology, 2008, 4(6): 357-365.
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Dual Inhibition of Cdc7 and Cdk9 by PHA-767491 Suppresses Hepatocarcinoma Synergistically with 5-Fluorouracil.[Pubmed:25643258]
Curr Cancer Drug Targets. 2015;15(3):196-204.
Activation of checkpoint kinase 1 (Chk1) is essential in chemoresistance of hepatocarcinoma (HCC) to 5-fluorouracil (5-FU) and other antimetabolite family of drugs. In this study, we demonstrated that PHA-767491, a dual inhibitor of two cell cycle checkpoint kinases, cell division cycle kinase 7 (Cdc7) and cyclin-dependent kinase 9 (Cdk9), has synergistic antitumor effect with 5-FU to suppress human HCC cells both in vitro and in vivo. Compared with the sole use of each agent, PHA-767491 in combination with 5-FU exhibited much stronger cytotoxicity and induced significant apoptosis manifested by remarkably increased caspase 3 activation and poly(ADP-Ribose) polymerase fragmentation in HCC cells. PHA-767491 directly counteracted the 5-FU-induced phosphorylation of Chk1, a substrate of Cdc7; and decreased the expression of the anti-apoptotic protein myeloid leukemia cell 1, a downstream target of Cdk9. In tumor tissues sectioned from nude mice HCC xenografts, administration of PHA-767491 also decreased Chk1 phosphorylation and increased in situ cell apoptosis. Our study suggests that PHA- 767491 could enhance the efficacy of 5-FU by inhibiting Chk1 phosphorylation and down-regulating Mcl1 expression through inhibition of Cdc7 and Cdk9, thus combinational administration of PHA-767491 with 5-FU could be potentially beneficial to patients with advanced and resistant HCC.
Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness.[Pubmed:27891063]
Cancer Cell Int. 2016 Nov 18;16:88.
BACKGROUND: Genomic instability is a hallmark of cancer cells, and this cellular phenomenon can emerge as a result of replicative stress. It is possible to take advantage of replicative stress, and enhance it in a targeted way to fight cancer cells. One of such strategies involves targeting the cell division cycle 7-related protein kinase (CDC7), a protein with key roles in regulation of initiation of DNA replication. CDC7 overexpression is present in different cancers, and small molecule inhibitors of the CDC7 have well-documented anti-tumor effects. Here, we aimed to test the potential of CDC7 inhibition as a new strategy for glioblastoma treatment. METHODS: PHA-767491 hydrochloride was used as the CDC7 inhibitor. Two glioblastoma cell lines (U87-MG and U251-MG) and a control cell line (3T3) were used to characterize the effects of CDC7 inhibition. The effect of CDC7 inhibition on cell viability, cell proliferation, apoptosis, migration, and invasion were analyzed. In addition, real-time PCR arrays were used to identify the differentially expressed genes in response to CDC7 inhibition. RESULTS: Our results showed that CDC7 inhibition reduces glioblastoma cell viability, suppresses cell proliferation, and triggers apoptosis in glioblastoma cell lines. In addition, we determined that CDC7 inhibition also suppresses glioblastoma cell migration and invasion. To identify molecular targets of CDC7 inhibition, we used real-time PCR arrays, which showed dysregulation of several mRNAs and miRNAs. CONCLUSIONS: Taken together, our findings suggest that CDC7 inhibition is a promising strategy for treatment of glioblastoma.