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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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Purity: ≥98%
MK-8033 HCl is a novel, potent, selective, ATP competitive small-molecule, dual inhibitor of c-Met/Ron (IC50=1 nM Wt c-Met) under investigation as a treatment for cancer. The goal of developing MK-8033 was to lessen the time-dependent inhibition of CYP3A4 (TDI) that individuals in this structural class exhibit. To obtain MK-8033 and its analogues, a unique two-step protocol for the synthesis of benzylic sulfonamides was created. Crucially, MK-8033 completely inhibits the growth of tumors in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model. This is noteworthy because, unlike c-Met inhibitors that do not preferentially bind to the active kinase conformation, MK-8033 exhibits equal potency against a panel of oncogenic activating mutations of c-Met.
Targets |
Ron (IC50 = 27 nM)
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ln Vitro |
MK-8033 (Compound 11r, 10 μM) showed a 31% CYP3A4 (cytochrome P450 3A4) inhibition[1].
MK-8033 (1 μM, 2 h) inhibits the c-Met-dependent gastric cancer cell line GTL-16's Y1349 phosphorylation (IC50: 0.03 μM)[1]. MK-8033 (1-10 μM, 72 h) suppresses the growth of GTL-16 cells (IC50: 0.58 μM)[1]. MK-8033 inhibits oncogenic c-Met activation loop mutants with IC50s ranging from 0.6 to 1 nM. It binds more tightly to phosphorylated c-Met (Kd: 3.2 nM) than to its unphosphorylated counterpart (Kd: 10.4 nM).[1] MK-8033 (0.1-10 μM, 2 h) decreases c-Met, ERK, and Akt phosphorylation in EBC-1 and H1993 cells[2]. MK-8033 (1 μM, 1 h) increases the radiation sensitivity of high c-Met-expressing H1993 and EBC-1 cells[2]. MK-8033 (10 μM, 6 h) reduces DNA repair and increases γ-H2Ax levels in comparison to double irradiation in A549 cells[2]. MK-8033 (2 μM, 72 h) causes G-alpha protein mutant UM (uveal melanoma) cells to proliferate less, but induces apoptosis somewhat[3]. |
ln Vivo |
MK-8033 (Compound 11r, oral administration, 3-100 mg/kg, twice daily for 21 days) inhibits tumor growth in GTL-16 c-Met amplified gastric tumor xenografts[1].
MK-8033 shows good bioavailability (35% for rats, 33% for dogs) and moderate clearance (t1/2: 0.8 h for rats, 3.1 h for dogs)[1]. |
Cell Assay |
Cell Line: EBC-1, H1993 cells, A549 and H460 cells
Concentration: 0.1, 1, 10 μM Incubation Time: 2 h Result: Reduced the phosphorylation of c-Met, ERK, and Akt in EBC-1 and H1993 cells in a dose-dependent manner. |
Animal Protocol |
Human GTL-16 c-Met amplified gastric tumor xenografts
3, 10, 30, and 100 mg/kg Oral administration, twice daily for 21 days |
References |
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Molecular Formula |
C25H22CLN5O3S
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Molecular Weight |
507.991882801056
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Exact Mass |
507.1131884
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CAS # |
1283000-43-0
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Related CAS # |
MK-8033;1001917-37-8
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Appearance |
Solid
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SMILES |
CN1C=C(C=N1)C2=CC3=C(C=CC4=C(C3=O)C=C(C=C4)CS(=O)(=O)NCC5=CC=CC=N5)N=C2.Cl
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InChi Key |
BKIQDRGTLKPYCL-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C25H21N5O3S.ClH/c1-30-15-20(13-28-30)19-11-23-24(27-12-19)8-7-18-6-5-17(10-22(18)25(23)31)16-34(32,33)29-14-21-4-2-3-9-26-21;/h2-13,15,29H,14,16H2,1H3;1H
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Chemical Name |
1-[5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-14-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide;hydrochloride
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Synonyms |
MK-8033; MK8033; MK 8033; MK-8033 hydrochloride; MK8033 HCL
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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) |
H2O: ~7.1 mg/mL (~14.1 mM)
DMSO: ~5.9 mg/mL (~11.6 mM) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.59 mg/mL (1.16 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 5.9 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: ≥ 0.59 mg/mL (1.16 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 5.9 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.  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.9685 mL | 9.8427 mL | 19.6854 mL | |
5 mM | 0.3937 mL | 1.9685 mL | 3.9371 mL | |
10 mM | 0.1969 mL | 0.9843 mL | 1.9685 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.
MK-8033 affects c-Met–induced signaling in EBC-1 and H1993 cells but not in A549 and H460 cells. Radiation induces c-Met expression and radiosensitizes A549 and H460 cells. th> |
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MK-8033 radiosensitizes EBC-1 and H1993 cells but not A549 and H460 NSCLC cells. A 1-hour pretreatment with MK-8033 (1 μM) radiosensitized NSCLC cells with high basal c-Met levels (EBC-1 and H1993) but not in low c-Met-expressing cells.J Thorac Oncol.2012 Aug;7(8):1211-7. td> |
A, MK-8033 reduces p-c-Met levels in A549 cells after radiation. A single dose of radiation did not affect the expression of phosphorylated (activated) c-Met, but fractionated radiation (i.e., two doses) did. This increase was attenuated by the addition of MK-8033 (10μM, 2 hours after first radiation) between the two radiation doses.J Thorac Oncol.2012 Aug;7(8):1211-7. td> |