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| 5mg |
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| 10mg |
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| 25mg |
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| 100mg |
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SCH900776 S-isomer is the S-isomer of SCH900776 (MK-8776), which is a novel, highly potent and selective Chk1(cell cycle checkpoint kinase 1) inhibitor with IC50 of 3 nM in a cell-free assay. In contrast to Chk2, it exhibits 500-fold selectivity. There may be chemosensitization and radiosensitization activities for the agent SCH900776 (MK-8776). Tumor cells may use MK-8776 to avoid Chk1-dependent cell cycle arrest in the S and G2/M phases and instead undergo DNA repair before entering mitosis. This could make the tumor cells more vulnerable to the DNA-damaging effects of ionizing radiation and alkylating chemotherapeutic agents. MK-8776 specifically binds to and inhibits Chk1.
| Targets |
Chk1 (IC50 = 3 nM); CDK2 (IC50 = 0.16 μM)
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|---|---|
| ln Vitro |
SCH 900776 is a less effective inhibitor of CDK2 and Chk2, with IC50 values of 0.16 μM and 1.5 μM, respectively. The human liver microsomal isoforms of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 are not significantly inhibited by SCH 900776. Twenty-four hours after exposure to hydroxyurea, SCH 900776 causes a dose-dependent loss of DNA replication capacity. SCH 900776 increases the hydroxyurea, 5-fluoruracil, and cytarabine γ-H2AX response. When SCH 900776 is combined with an antimetabolite, it causes γ-H2AX to accumulate in less than two hours, which is a sign of double stranded DNA breaks and replication fork collapse. Moreover, SCH 900776 dose-dependently inhibits the build-up of Chk1 pS296 autophosphorylation. Following exposure to SCH 900776, cycling populations of normal cells induce Chk1 pS345 as part of a futile cycle, possibly driven by AT-family kinases and DNA-PK. This rapid, dose-dependent accumulation of Chk1 pS345 is associated with exposure of proliferating WS1 cells to SCH 900776.[1]
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| ln Vivo |
When SCH 900776 is administered half an hour after gemcitabine, 4 mg/kg is enough to cause the γ-H2AX biomarker, and 8 mg/kg produces better tumor pharmacodynamic and regression responses than either SCH 900776 or gemcitabine alone. Increases in SCH 900776 dosage (16 mg/kg and 32 mg/kg) cause tumor response to improve gradually. Crucially, in BALB/c mice, doses of SCH 900776 that are linked to strong biomarker activation and better tumor response are not linked to increased gemcitabine toxicity on hematological parameters.[1]
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| Enzyme Assay |
An in vitro experiment employing biotinylated peptide based on CDC25C as the substrate and recombinant His-Chk1 expressed in the baculovirus expression system as an enzyme source. In kinase buffer containing 50 mM Tris pH8.0, 10 mM MgCl2, and 1 mM DTT, His-Chk1 is diluted to 32 nM. The CDC25C (CDC25 Ser216 C-term biotinylated peptide) peptide is diluted in kinase buffer to a concentration of 1.93 μM. In order to create the final reaction concentrations of 6.2 nM Chk1, 385 nM CDC25C, and 1% DMSO following the addition of the start solution, 20 μL of 32 nM Chk1 enzyme solution and 20 μL of 1.926 μM CDC25C are mixed and combined with 10 μL of SCH 900776 diluted in 10% DMSO for each kinase reaction. Addition of 50 μL of start solution, which contains 2 μM ATP and 0.2 μCi of 33P-ATP, initiates the reaction, resulting in a final reaction concentration of 1 μM ATP and 0.2 μCi of 33P-ATP per reaction. Kinase reactions run for 2 hours at room temperature and are stopped by the addition of 100 μL of stop solution consisting of 2 M NaCl, 1% H3PO4, and 5 mg/mL Streptavidin-coated SPA beads. Filtermate universal harvester in combination with a 96-well GF/B filter plate is used to collect SPA beads. Both two M NaCl and two M NaCl with 1% phosphoric acid are used to wash the beads twice. After that, the signal is measured with a TopCount 96-well liquid scintillation counter. Sequential dilutions of SCH 900776 at eight points in duplicate are used to create dose-response curves. By using nonlinear regression analysis, IC50 values are obtained.
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| Cell Assay |
Cells were treated with inhibitors or vehicle for 1 hour.
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| Animal Protocol |
Female nude mice injected subcutaneously with A2780 or MiaPaCa2 cells
~50 mg/kg Administered intraperitoneally |
| References |
| Molecular Formula |
C₁₅H₁₈BRN₇
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|---|---|
| Molecular Weight |
376.25
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| Exact Mass |
375.08
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| Elemental Analysis |
C, 47.88; H, 4.82; Br, 21.24; N, 26.06
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| CAS # |
891494-64-7
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| Related CAS # |
SCH900776;891494-63-6
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| Appearance |
white to off-white Solid powder
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| SMILES |
CN1C=C(C=N1)C2=C3N=C(C(=C(N3N=C2)N)Br)[C@H]4CCCNC4
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| InChi Key |
GMIZZEXBPRLVIV-VIFPVBQESA-N
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| InChi Code |
InChI=1S/C15H18BrN7/c1-22-8-10(6-19-22)11-7-20-23-14(17)12(16)13(21-15(11)23)9-3-2-4-18-5-9/h6-9,18H,2-5,17H2,1H3/t9-/m0/s1
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| Chemical Name |
6-bromo-3-(1-methylpyrazol-4-yl)-5-[(3S)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine
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| Synonyms |
MK 8776; MK8776; MK-8776; SCH900776; SCH 900776; SCH-900776
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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 |
| 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) |
DMSO: ~75 mg/mL (~199.3 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.64 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.5 mg/mL (6.64 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 25.0 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: ≥ 2.5 mg/mL (6.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 4% DMSO+30% propylene glycol: 5 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6578 mL | 13.2890 mL | 26.5781 mL | |
| 5 mM | 0.5316 mL | 2.6578 mL | 5.3156 mL | |
| 10 mM | 0.2658 mL | 1.3289 mL | 2.6578 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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