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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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250mg |
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500mg |
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Purity: ≥98%
MK-8776 (also known as SCH900776; MK8776; SCH-900776; MK 8776) is a novel, highly potent and selective Chk1 (cell cycle checkpoint kinase 1) inhibitor with potential antineoplastic, radiosensitization and chemosensitization activities. In a cell-free assay, it inhibits Chk1 with an IC50 of 3 nM. Against Chk2, MK-8776 exhibits 500-fold selectivity. Tumor cells may avoid Chk1-dependent cell cycle arrest in the S and G2/M phases and instead undergo DNA repair before entering mitosis as a result of MK-8776's specific binding to and inhibition of Chk1. This could make tumor cells more vulnerable to the DNA-damaging effects of ionizing radiation and alkylating chemotherapeutic agents.
Targets |
Chk1 (IC50 = 3 nM); Chk2 (IC50 = 1500 nM); CDK2 (IC50 = 160 nM)
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ln Vitro |
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ln Vivo |
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Enzyme Assay |
General selectivity data for SCH 900776 against a variety of serine/threonine and tyrosine kinases is produced via the Kinase Profiler service. SCH 900776 is usually used in assays at two concentrations (0.5 and 5 μM) with a fixed (10 μM) concentration of ATP.
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Cell Assay |
In order to conduct cell growth assays, 500–1000 cells are seeded at a low density into 96-well plates, and the cells are then treated with the drug for a full day (8 wells per concentration). After treatment, cells are rinsed and cultured in new media at 37°C for five to seven days. The cells are lysed, cleaned, and stained with Hoechst 33258 before they reach confluence. Using a microplate spectrofluorometer, fluorescence is measured. The mean and standard error for the drug concentration that 50% inhibited growth are used to express the results.
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Animal Protocol |
Certain cell lines are grown in vitro, once they have been washed with PBS, they are resuspended in 50% Matrigel in PBS to a final concentration of 4×107 to 5×107 cells per mL for tumor implantation. A subcutaneous injection of 0.1 mL of this suspension is given to naked mice in the flank area. Tumor length (L), width (W), and height (H) are measured twice a week on each mouse using a caliper. The tumor volume is then determined using the formula (L×W×H)/2. Ten animals are randomly assigned to treatment groups and given intraperitoneally either SCH 900776 (formulated in 20% hydroxypropyl β-cyclodextrin) or specific chemotherapeutic agents, prepared in accordance with recommended guidelines. Measurements are taken both during and after the treatment phases of the tumor volumes and body masses. Prior to normalization to starting volume, data are recorded as means±SEM. In some experiments, time to progression to 10x starting volume, or TTP 10x, is recorded. The tumor and surrounding skin are removed during necropsy, preserved for an overnight period in 10% formalin, and then cleaned and preserved in 70% ethanol for pharmacodynamic marker analyses in mice. Shave an area about 4 square inches in size in order to perform skin punch biopsies. In order to induce local anesthesia in dogs, lidocaine is administered subcutaneously, while inhaled isofluorane is used for anesthesia in rats. Using a 4 mm biopsy punch, samples are obtained. Before being cleaned or stored in 70% ethanol, skin punches are fixed in 10% formalin for an entire night.
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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 # |
891494-63-6
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Related CAS # |
SCH900776 (S-isomer);891494-64-7
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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-SECBINFHSA-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-/m1/s1
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Chemical Name |
6-bromo-3-(1-methylpyrazol-4-yl)-5-[(3R)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine
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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: ≥ 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.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT00779584 | Completed | Drug: MK-8776 Drug: Gemcitabine |
Hodgkin Disease Neoplasms |
Merck Sharp & Dohme LLC | October 17, 2008 | Phase 1 |
NCT01870596 | Completed | Drug: CHK1 Inhibitor SCH 900776 Drug: Cytarabine |
Adult Acute Monocytic Leukemia Adult Erythroleukemia |
National Cancer Institute (NCI) |
May 2013 | Phase 2 |
NCT00907517 | Completed | Drug: MK-8776 Drug: Cytarabine |
Myelogenous Leukemia, Acute Leukemia, Lymphocytic, Acute |
Merck Sharp & Dohme LLC | July 29, 2009 | Phase 1 |
Comparative efficacy of UCN-01 and SCH900776 at inhibiting Chk1 and abrogating SN38-induced cell cycle arrest.Mol Cancer Ther.2012 Feb;11(2):427-38. th> |
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The impact of checkpoint inhibitors on sensitivity of cells to SN38, hydroxyurea and cisplatin.Mol Cancer Ther.2012 Feb;11(2):427-38. td> |
Analysis of cell cycle perturbation induced by hydroxyurea.Mol Cancer Ther.2012 Feb;11(2):427-38. td> |
Impact of concentration and schedule of hydroxyurea and SCH900776 on DNA damage and cytotoxicityA.Mol Cancer Ther.2012 Feb;11(2):427-38. th> |
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Comparative efficacy of UCN-01 and SCH900776 at abrogating SN38-induced cell cycle arrest in cells suppressed for Chk1.A.MDA-MB-231ΔChk1 cells were incubated with 10 ng/mL SN38 for 24 h.Mol Cancer Ther.2012 Feb;11(2):427-38. td> |