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    MK-2461
    MK-2461

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0575
    CAS #: 917879-39-1Purity ≥98%

    Description: MK-2461 (MK2461) is a novel, potent, ATP-competitive, multi-targeted inhibitor for c-Met (WT/mutants) with potential antineoplastic activity. It inhibits various mutants of c-Met with IC50 of 0.4-2.5 nM, and is less potent against other kinases such as Ron, Flt1. MK-2461 exhibits 8- to 30-fold greater selectivity for inhibiting c-Met over FGFR1, FGFR2, FGFR3, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB. MKIn tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinase–AKT and Ras–extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop.

    References: Cancer Res. 2010 Feb 15;70(4):1524-33; Anal Biochem. 1999 Apr 10;269(1):94-104.

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    Molecular Weight (MW)495.55
    FormulaC24H25N5O5S
    CAS No.917879-39-1
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 99 mg/mL (199.8 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)1% DMSO+30% polyethylene glycol+1% Tween 80, pH 4: 15mg/mL
    SynonymsMK 2461; MK-2461; MK2461;  

    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

    InChi Key: JGEBLDKNWBUGRZ-HXUWFJFHSA-N

    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

    SMILES Code: O=S(NC1=CC=C2C(C(C3=CC(C4=CN(C)N=C4)=CN=C3C=C2)=O)=C1)(N(C[[email protected]]5OCCOC5)C)=O


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    In Vitro

    In vitro activity: 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 PDGFRα (Y849) in H1703 cells with IC50 of<0.3 μM. 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 ~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.


    Kinase Assay: The c-Met–catalyzed phosphorylation of N-biotinylated peptide (EQEDEPEGDYFEWLE-CONH2) is measured using a time-resolved fluorescence resonance energy transfer assay. The MK-2461 IC50 for Ron, Mer, Flt1, Flt3, Flt4, KDR, PDGFRβ, FGFR1, FGFR2, FGFR3, TrkA, and TrkB are determined using time-resolved fluorescence resonance energy transfer assays similar to the c-Met kinase assay.


    Cell Assay: Cells (SW480, HT29, SW620, Colo 205, HCT116, HCT15, Colo 201, SCC-9, H1993, H1048, GTL-16, SNU15, et al.) are exposed to various concentrations of MK-2461 for 72 hours. The viability of tumor cells is measured using the ViaLight PLUS kit.

    In VivoMK-2461 treatment significantly inhibits c-Met (Y1349) phosphorylation in GTL-16 tumors with IC50 of ~1 μM. 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.
    Animal modelFemale nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells
    Formulation & DosageDissolved in DMSO, and diluted in saline; 134 mg/kg; Oral gavage 
    References

    Cancer Res. 2010 Feb 15;70(4):1524-33; Anal Biochem. 1999 Apr 10;269(1):94-104.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    MK-2461

    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

    MK-2461 effectively inhibited phosphorylation of the activation loop of FGFR2 and PDGFR in cells. Cancer Res. 2010 Feb 15;70(4):1524-33.

    MK-2461

    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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