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| 25mg |
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Purity: ≥98%
MK-2461 (MK2461) is a novel, potent, ATP-competitive, multi-targeted inhibitor for c-Met (WT/mutants) with potential antineoplastic activity. With an IC50 of 0.4-2.5 nM, it inhibits a range of c-Met mutants and has a lower potency against kinases like Ron and Flt1. When it comes to inhibiting c-Met, MK-2461 is 8–30 times more selective than FGFR1, FGFR2, FGFR3, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB. NK MK-2461 efficiently inhibited autophosphorylation of the c-Met activation loop while suppressing constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, as well as its downstream signaling to the phosphoinositide 3-kinase–AKT and Ras–extracellular signal-regulated kinase pathways in tumor cells.
| Targets |
c-Met(M1250T) (IC50 = 0.4 nM); c-Met(Y1235D) (IC50 = 0.5 nM); c-Met(Y1230H) (IC50 = 1.0 nM); c-Met(N1100) (IC50 = 1.5 nM); c-Met(Y1230C) (IC50 = 1.5 nM)
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| ln Vitro |
MK-2461 additionally has IC50 values of 65 nM, 39 nM, 50 nM, 44 nM, 46 nM, 61 nM, and 78 nM for FGFR1, FGFR2, FGFR3, KDR, TrkA, TrkB, and Flt4, respectively. With IC50 values of 1.5 nM, 1.5 nM, 1.0 nM, 0.5 nM, and 0.4 nM, respectively, MK-2461 more effectively suppresses the activity of oncogenic c-Met kinase mutants, including N1100Y, Y1230C, Y1230H, Y1235D, and M1250T, in comparison to wild-type c-Met. Phosphorylated c-Met is more strongly bound by MK-2461 than unphosphorylated c-Met. MK-2461 effectively prevents ATP from causing the c-Met'sCOOH-terminaldocking domain to become autophosphorylated, but not the activation loop. On the other hand, MK-2461 has an IC50 of less than 0.3 μM and prevents phosphorylation of PDGFRα (Y849) in H1703 cells and the activation loop of FGFR2 (Y653/Y654) in Kato III cells. MK-2461 inhibits HGF-induced branching tubulogenesis of MDCK cells, HGF-induced migration of HPAF II cells (IC50 of 404 nM), and HGF-induced mitogenesis of 4MBr-5 cells (IC50 of 204 nM). Furthermore, with an IC50 of approximately 100 nM, MK-2461 effectively suppresses the IL-3-independent proliferation of 32D cells transformed with Tpr-Met or Tpr-Met (Y362C) mutant. A wide panel of tumor cell lines is considerably inhibited in growth by MK-2461, which is particularly effective against tumor cells that have MET or FGFR2 genomic amplification.[1]
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| ln Vivo |
MK-2461 treatment, with an IC50 of approximately 1 μM, significantly inhibits the phosphorylation of c-Met (Y1349) in GTL-16 tumors. MK-2461 can effectively suppress the growth of GTL-16 xenograft tumors in mice by 62%, 77%, 75%, and 90% when given orally at doses of 10 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg once daily. The growth of NIH3T3 tumors containing the c-Met single nucleotide mutants T3936C and T3997C is similarly inhibited by MK-2461 treatment at 134 mg/kg twice daily, by 78% and 62%, respectively.[1]
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| Enzyme Assay |
EQEDEPEGDYFEWLE-CONH2 phosphorylation is measured by means of a time-resolved fluorescence resonance energy transfer assay. This phosphorylation is catalyzed by c-Met. In [2] Timing-resolved fluorescence resonance energy transfer assays, akin to the c-Met kinase assay, are used to determine the MK-2461 IC50 for Ron, Mer, Flt1, Flt3, Flt4, KDR, PDGFRβ, FGFR1, FGFR2, FGFR3, TrkA, and TrkB.
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| Cell Assay |
For 72 hours, cells are exposed to different MK-2461 concentrations. The ViaLight PLUS kit is used to measure the viability of tumor cells.
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| Animal Protocol |
Female nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells
~134 mg/kg Orally once or twice daily |
| References | |
| Additional Infomation |
MK-2461 is a member of the class of benzocycloheptapyridines that is 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one substituted by 1-methyl-1H-pyrazol-4-yl and [{[(2R)-1,4-dioxan-2-yl]methyl}(methyl)sulfamoyl]amino groups at positions 3 and 7, respectively. It is a novel ATP-competitive multi-targeted inhibitor of activated c-Met (IC50 = 2.5 nM). It has a role as an antineoplastic agent, a c-Met tyrosine kinase inhibitor and an apoptosis inducer. It is a member of pyrazoles, a benzocycloheptapyridine, a member of dioxanes and a member of sulfamides.
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| Molecular Formula |
C24H25N5O5S
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| Molecular Weight |
495.55
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| Exact Mass |
495.157
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| Elemental Analysis |
C, 58.17; H, 5.09; N, 14.13; O, 16.14; S, 6.47
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| CAS # |
917879-39-1
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| Related CAS # |
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| PubChem CID |
44137946
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
732.4±70.0 °C at 760 mmHg
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| Flash Point |
396.7±35.7 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.693
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| LogP |
-0.52
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
895
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C1C2C=C(C=CC=2C=CC2N=CC(C3C=NN(C)C=3)=CC1=2)NS(=O)(=O)N(C)C[C@H]1OCCOC1
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| InChi Key |
JGEBLDKNWBUGRZ-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C24H25N5O5S/c1-28-13-18(12-26-28)17-9-22-23(25-11-17)6-4-16-3-5-19(10-21(16)24(22)30)27-35(31,32)29(2)14-20-15-33-7-8-34-20/h3-6,9-13,20,27H,7-8,14-15H2,1-2H3/t20-/m1/s1
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| Chemical Name |
14-[[[(2R)-1,4-dioxan-2-yl]methyl-methylsulfamoyl]amino]-5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene
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| Synonyms |
MK 2461; MK-2461; MK2461
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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 (5.04 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 (5.04 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: 1% DMSO+30% polyethylene glycol+1% Tween 80, pH 4: 15mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0180 mL | 10.0898 mL | 20.1796 mL | |
| 5 mM | 0.4036 mL | 2.0180 mL | 4.0359 mL | |
| 10 mM | 0.2018 mL | 1.0090 mL | 2.0180 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 |
| NCT00496353 | Completed | Drug: MK2461 | Neoplasm | Merck Sharp & Dohme LLC | June 2007 | Phase 1 Phase 2 |
| NCT00518739 | Completed | Drug: MK2461 | Advanced Cancer | Merck Sharp & Dohme LLC | February 2007 | Phase 1 |
Differential effects of MK-2461 on phosphorylation of key tyrosine residues of c-Met. Cancer Res. 2010 Feb 15;70(4):1524-33. |
MK-2461 effectively inhibited phosphorylation of the activation loop of FGFR2 and PDGFR in cells. Cancer Res. 2010 Feb 15;70(4):1524-33. |
Orally administered MK-2461 inhibited c-Met phosphorylation and xenograft tumor growth in nude mice. Cancer Res. 2010 Feb 15;70(4):1524-33. |
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