MK-2461

Catalog No.S2774 Batch:S277401

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Technical Data

Formula

C24H25N5O5S
Molecular Weight 495.55 CAS No. 917879-39-1
Solubility (25°C)* In vitro DMSO 99 mg/mL (199.77 mM)
Water Insoluble
Ethanol Insoluble
In Vivo (Add solvents to the product individually and in order.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description MK-2461 is a potent, multi-targeted inhibitor for c-Met(WT/mutants) with IC50 of 0.4-2.5 nM, less potent to Ron, Flt1; 8- to 30-fold greater selectivity of c-Met targets versus FGFR1, FGFR2, FGFR3, PDGFReta, KDR, Flt3, Flt4, TrkA, and TrkB. Phase 1/2.
Targets
c-Met (M1250T) c-Met (Y1235D) c-Met (Y1230H) c-Met (N1100) c-Met (Y1230C) View More
0.4 nM 0.5 nM 1.0 nM 1.5 nM 1.5 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, this compound 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. It binds more strongly to phosphorylated c-Met than to unphosphorylated c-Met. This chemical potently inhibits ATP-induced autophosphorylation of the COOH-terminal docking domain of c-Met, but not the activation loop. In contrast, it inhibits phosphorylation of the activation loop of FGFR2 (Y653/Y654) in Kato III cells and PDGFR (Y849) in H1703 cells with IC50 of <0.3 M. It 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, this compound potently inhibits IL-3-independent proliferation of 32D cells transformed with Tpr-Met or Tpr-Met (Y362C) mutant with IC50 of ~100 nM. It significantly inhibits the proliferation of a large panel of tumor cell lines, especially potent against tumor cells harbored genomic amplification of MET or FGFR2.
In Vivo MK-2461 treatment significantly inhibits c-Met (Y1349) phosphorylation in GTL-16 tumours with IC50 of ~1 M. Oral administration of this compound at 10 mg/kg, 50 mg/kg, and 100 mg/kg twice daily as well as 200 mg/kg once daily effectively suppresses tumour growth of GTL-16 xenografts in mice by 62%, 77%, 75%, and 90%, respectively. Similarly, this chemical treatment at 134 mg/kg twice daily inhibits the growth of NIH3T3 tumours harbouring c-Met single nucleotide mutants T3936C and T3997C, by 78% and 62%, respectively.
Features Preferentially binds to activated c-Met, distinguished from other known ATP-competitive tyrosine kinase inhibitors (which bind to inactive and active kinases with similar affinity).

Protocol (from reference)

Kinase Assay:[1]
  • 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. The IC50 of this compound for Ron, Mer, Flt1, Flt3, Flt4, KDR, PDGFReta, 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:[1]
  • Cell Lines

    SW480, HT29, SW620, Colo 205, HCT116, HCT15, Colo 201, SCC-9, H1993, H1048, GTL-16, SNU15, et al.

  • Concentrations

    Dissolved in DMSO, final concentrations ~100 μM

  • Incubation Time

    72 hours

  • 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.
Animal Study:[1]
  • Animal Models

    Female nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells

  • Dosages

    ~134 mg/kg

  • Administration

    Orally once or twice daily

References

  • https://pubmed.ncbi.nlm.nih.gov/20145145/
  • https://pubmed.ncbi.nlm.nih.gov/10094779/

Customer Product Validation

Both V-H cells and V-J cells are treated with MK-2461, XL-184 or ABT-869, respectively. (i-k) Western blot analysis of sFlt-1 expression after incubation with three VEGF-A receptor inhibitors or in the control.

Data from [ , , Mol Cell Biochem, 2018, doi: 10.1007/s11010-018-3337-5 ]

Sellecks MK-2461 Has Been Cited by 4 Publications

Feed-forward activation of STAT3 signaling limits the efficacy of c-Met inhibitors in esophageal squamous cell carcinoma (ESCC) treatment [ Mol Carcinog, 2021, 60(7):481-496] PubMed: 34018249
Met is required for oligodendrocyte progenitor cell migration in Danio rerio [ G3 (Bethesda), 2021, 11(10)jkab265] PubMed: 34568921
VEGF-A regulates sFlt-1 production in trophoblasts through both Flt-1 and KDR receptors [Xiao Z Mol Cell Biochem, 2018, 449(1-2):1-8] PubMed: 29497919
MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells [ Pancreas, 2017, 46(4):557-566] PubMed: 28196027

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

NOT FOR HUMAN, VETERINARY DIAGNOSTIC OR THERAPEUTIC USE.