ArtNr |
S2774-1000 |
Hersteller |
Selleckchem
|
CAS-Nr. |
917879-39-1 |
Menge |
1 g |
Kategorie |
|
Typ |
Inhibitors |
Specific against |
other |
ECLASS 10.1 |
32160490 |
ECLASS 11.0 |
32160490 |
UNSPSC |
12000000 |
Alias |
917879-39-1' |
Similar products |
MK-2461 |
Lieferbar |
|
Administration |
Orally once or twice daily |
Animal Models |
Female nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells |
Cell lines |
SW480, HT29, SW620, Colo 205, HCT116, HCT15, Colo 201, SCC-9, H1993, H1048, GTL-16, SNU15, et al. |
Chemical Name |
N-((2R)-1, 4-Dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4, 5]cyclohepta[1, 2-b]pyridin-7-yl]sulfamide |
Clinical Trials |
A Phase I/II study of MK-2461 in patients with advanced solid tumors has been completed. |
Concentrations |
Dissolved in DMSO, final concentrations ca.100 uM |
Description |
MK-2461 is a potent inhibitor of c-Met, Ron, Flt1/3, PDGFRbeta, Mer and FGFR1/2/3 with IC50 of 2.5 nM, 7 nM, 10 nM/22 nM, 22 nM, 24 nM and 65 nM/39 nM/50 nM, respectively. |
Dosages |
ca.134 mg/kg |
Features |
MK-2461 preferentially binds to the activated c-Met, distinguished from other known ATP-competitive tyrosine kinase inhibitors, which either bind to the unactivated and active kinase with similar affinity or preferentially bind the unactivated kinase. |
Formulation |
Dissolved in DMSO, and diluted in saline |
IC50 |
2.5 nM, 2.5 nM, 2.5 nM, 2.5 nM, 2.5 nM, 2.5 nM |
In vitro |
MK-2461 also potently inhibits FGFR1, FGFR2, FGFR3, KDR, TrkA, TrkB, and Flt4 with IC50 of 65 nM, 39 nM, 50 nM, 44 nM, 46 nM, 61 nM, and 78 nM, respectively. Compared with wild-type c-Met, MK-2461 more potently inhibits the activity of oncogenic c-Met kinase mutants such as N1100Y, Y1230C, Y1230H, Y1235D, and M1250T with IC50 of 1.5 nM, 1.5 nM, 1.0 nM, 0.5 nM, and 0.4 nM, respectively. MK-2461 binds more strongly to phosphorylated c-Met than to unphosphorylated c-Met. MK-2461 potently inhibits ATP-induced autophosphorylation of the COOH-terminal docking domain of c-Met, but not the activation loop. In contrast, MK-2461 inhibits phosphorylation of the activation loop of FGFR2 (Y653/Y654) in Kato III cells and PDGFRalpha (Y849) in H1703 cells with IC50 of <0.3 uM. MK-2461 inhibits HGF-induced mitogenesis of 4MBr-5 cells with IC50 of 204 nM, and HGF-induced migration of HPAF II cells with IC50 of 404 nM, as well as HGF-induced branching tubulogenesis of MDCK cells. In addition, MK-2461 potently inhibits IL-3-independent proliferation of 32D cells transformed with Tpr-Met or Tpr-Met (Y362C) mutant with IC50 of ca.100 nM. MK-2461 significantly inhibits the proliferation of a large panel of tumor cell lines, especially potent against tumor cells harbored genomic amplification of MET or FGFR2. [1] |
In vivo |
MK-2461 treatment significantly inhibits c-Met (Y1349) phosphorylation in GTL-16 tumors with IC50 of ca.1 uM. Oral administration of MK-2461 at 10 mg/kg, 50 mg/kg, and 100 mg/kg twice daily as well as 200 mg/kg once daily effectively suppresses tumor growth of GTL-16 xenografts in mice by 62%, 77%, 75%, and 90%, respectively. Similarly, MK-2461 treatment at 134 mg/kg twice daily inhibits the growth of NIH3T3 tumors harboring c-Met single nucleotide mutants T3936C and T3997C, by 78% and 62%, respectively. [1] |
Incubation Time |
72 hours |
Kinase Assay |
Time-resolved fluorescence resonance energy transfer assay, The c-Met–catalyzed phosphorylation of N-biotinylated peptide (EQEDEPEGDYFEWLE-CONH2) is measured using a time-resolved fluorescence resonance energy transfer assay. [2] The MK-2461 IC50 for Ron, Mer, Flt1, Flt3, Flt4, KDR, PDGFRbeta, FGFR1, FGFR2, FGFR3, TrkA, and TrkB are determined using time-resolved fluorescence resonance energy transfer assays similar to the c-Met kinase assay. |
Method |
Cells are exposed to various concentrations of MK-2461 for 72 hours. The viability of tumor cells is measured using the ViaLight PLUS kit. |
Molecular Weight (MW) |
495, 55 |
Picture ChemicalStructure Description |
MK-2461 Chemical Structure |
Solubility (25C) |
DMSO 99 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL |
Storage |
2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO |
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