MK-2461 is a potent inhibitor of c-Met, Ron, Flt1, Flt 3, PDGFRβ, and Mer with IC50 of 2.5 nM, 7 nM, 10 nM, 22 nM, 22 nM, and 24 nM, respectively. MK-2461 also exhibits significant activities toward several other kinases including 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. MK-2461 preferentially binds to the activated c-Met, and is slightly more potent against five naturally occurring oncogenic human c-Met mutants (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) compared with wild-type c-Met. MK-2461 significantly inhibits constitutive and ligand-induced phosphorylation of the juxtamembrane domain (Y1003) and the COOH-terminal docking site (Y1349/Y1365) of c-Met, as well as phosphorylation of AKT (S473) and ERK1/2 (T202/Y204), without affecting c-Met activation loop (Y1234/35) phosphorylation in GTL-16 cells. MK-2461 displays potent antiproliferative activity against a variety of tumor cell lines with IC50 of 0.1-30 μM. Orally administered MK-2461 inhibits c-Met phosphorylation in vivo, and tumor growth of GTL-16 xenografts, as well as the growth of NIH3T3 tumors harboring murine equivalents of human c-Met Y1230H and M1250T mutants.
| Cell Experiment | |
|---|---|
| Cell lines | SW480, HT29, SW620, Colo 205, HCT116, HCT15, Colo 201, SCC-9, H1993, H1048, GTL-16, SNU15, et al. |
| Preparation method | Exposing cells to various concentrations of MK-2461 for 72 hours. Using the ViaLight PLUS kit to mearsure the viability of tumor cells . |
| Concentrations | Dissolved in DMSO, final concentrations ~100 μM |
| Incubation time | 72 hours |
| Animal Experiment | |
|---|---|
| Animal models | Female nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells |
| Formulation | Dissolved in DMSO, and diluted in saline |
| Dosages | ~134 mg/kg |
| Administration | Orally once or twice daily |
| Molecular Weight | 495.55 |
| Formula | C24H25N5O5S |
| CAS Number | 917879-39-1 |
| Solubility (25°C) | DMSO 90 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related c-Met Products |
|---|
| SU 5616
SU 5616 is an organic compound. |
| MET/PDGFRA-IN-2
MET/PDGFRA-IN-2 is a MET and PDGFRA protein inhibitor. |
| MET/PDGFRA-IN-1
MET/PDGFRA-IN-1 is a MET and PDGFRA protein inhibitor (IC50: 36 μM for MET). |
| Canlitinib
Canlitinib is a tyrosine kinase inhibitor, extracted from patent WO2018072614 (IV-2). |
| Norleual TFA
Norleual TFA, an angiotensin (Ang) IV analog, is a hepatocyte growth factor (HGF)/c-Met inhibitor with an IC50 of 3 pM. |
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