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| 5mg |
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| 25mg |
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Purity: ≥98%
PHA-767491 HCl (formerly known as CAY10572 HCl) is a novel potent ATP-competitive and dual CDC7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively. It exhibits selectivity of approximately 20 times against CDK1/2 and GSK3-β, 50 times against MK2 and CDK5, and 100 times against PLK1 and CHK2. An important kinase called CDC7 stimulates replication origins to facilitate DNA replication. PHA-767491 inhibits the synthesis of DNA and modifies the replicative DNA helicase's phosphorylation at CDC7-dependent phosphorylation sites. PHA-767491, in contrast to existing DNA synthesis inhibitors, inhibits replication origin activation without impeding replication fork progression or causing a prolonged DNA damage response. In preclinical cancer models, PHA-767491 treatment induces apoptotic cell death in a variety of cancer cell types and inhibits tumor growth. PHA-767491 is the first known molecule to directly influence the mechanisms governing initiation rather than elongation in DNA replication, and its actions imply that inhibiting Cdc7 kinase may be a novel approach to the development of anticancer treatments.
| Targets |
CDK9 (IC50 = 34 nM); CDK2 (IC50 = 240 nM); CDK1 (IC50 = 250 nM); CDK5 (IC50 = 460 nM); GSK3-β (IC50 = 220 nM); Mk2 (IC50 = 470 nM); Plk1 (IC50 = 980 nM); Chk2 (IC50 = 1100 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Increasing concentrations of each DDK inhibitor are pre-incubated for five minutes with 20 ng of purified human DDK. After adding 1.5 µM cold ATP and 10 µCi (γ)-32P ATP, the mixture is mixed with 50 mM Tris-HCl (pH 7.5), 10 mM MgCl2, and 1 mM DTT. It is then incubated for 30 minutes at 30°C. SDS-PAGE and autoradiography on HyBlot CL film are performed after the proteins are denatured in 1X Laemmli buffer at 100°C. One way to measure the kinase activity of DDK is to look for auto-phosphorylation. ImageJ is used to quantify 32P-labeled bands, and GraphPad is used to determine the IC50 values.
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| Cell Assay |
There are 2500 cells plated in each well of 96-well plates used for assays. Cells undergo treatment with small molecule inhibitors after 24 hours, and they are then incubated at 37°C for 72 hours. Next, the cells undergo lysis, and the CellTiter-Glo assay is employed to quantify the ATP content, which serves as a marker of metabolically active cells. Utilizing GraphPad software, IC50 values are determined. 100,000 cells are plated per well in six-well plates used for assays. Small molecule inhibitors are applied to the cells after a day, and they are then cultured for different lengths of time. The cells are trypsinized, and 5 milliliters of phosphate-buffered saline are used to create a suspension. A 10-minute room temperature incubation is conducted after mixing 30 µL of this suspension with 30 µL of CellTiter-Glo reagent. The BioTek Synergy Neo Microplate Reader and EnVision 2104 Multilabel Reader are used to measure luminosity.
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| Animal Protocol |
Female SCID mice subcutaneously implanted with HL60 cells, male Hsd, athymic nu-nu mice subcutaneously implanted with HCT116 cells, A2780 or Mx-1 cells, and female Sprague-Dawley rats with DMBA-induced mammary carcinomas
~50 mg/kg Intravenous or oral administration twice a day |
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| References |
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| Molecular Formula |
C12H11N3O.HCL
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| Molecular Weight |
249.7
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| Exact Mass |
249.0668897
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| Elemental Analysis |
C, 57.72; H, 4.84; Cl, 14.20; N, 16.83; O, 6.41.
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| CAS # |
942425-68-5
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| Related CAS # |
PHA-767491;845714-00-3
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| Appearance |
Solid powder
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| SMILES |
C1CNC(=O)C2=C1NC(=C2)C3=CC=NC=C3.Cl
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| InChi Key |
IMVNFURYBZMFDZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H11N3O.ClH/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);1H
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| Chemical Name |
2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one;hydrochloride
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (4.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1 mg/mL (4.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 5% DMSO+30% PEG 300+2% Tween 80+ddH2O: 1mg/mL Solubility in Formulation 4: 50 mg/mL (200.24 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.0048 mL | 20.0240 mL | 40.0481 mL | |
| 5 mM | 0.8010 mL | 4.0048 mL | 8.0096 mL | |
| 10 mM | 0.4005 mL | 2.0024 mL | 4.0048 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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