Capmatinib (INCB28060) is a potent, orally available selective inhibitor of the c-MET receptor tyrosine kinase, a clinically validated cancer target. Capmatinib (INCB28060) exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. INCB28060 potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. Capmatinib (INCB28060) potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and INCB28060 is well tolerated at doses that achieve complete tumor inhibition.
Cancer Res. 2017 Jan 1;77(1):41-52.
Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer
Capmatinib (INCB28060) purchased from AbMole
Mol Cancer Ther. 2017 Nov;16(11):2399-2409.
Dual inhibition of Hedgehog and c-Met pathways for pancreatic cancer treatment
Capmatinib (INCB28060) purchased from AbMole
Nature. 2015 Jun 18;522(7556):349-53.
MET is required for the recruitment of anti-tumoural neutrophils.
Capmatinib (INCB28060) purchased from AbMole
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Source | Mol Cancer Ther (2017). Figure 4. INCB28060 (Abmole Bioscience. Houston, TX, USA) |
| Method | oral gavage | |
| Cell Lines | KPC and orthotopic transplant model mice | |
| Concentrations | 1 mg/kg | |
| Incubation Time | 7, 14 or 21 days | |
| Results | Importantly, the group with dual inhibitor treatment in addition to gemcitabine showed no metastases. This result suggests that the combination of c-Met and Hh inhibitors in addition to gemcitabine has significantly suppressed metastasis formation. |
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Source | Mol Cancer Ther (2017). Figure 3. INCB28060 (Abmole Bioscience. Houston, TX, USA) |
| Method | oral gavage | |
| Cell Lines | KPC and orthotopic transplant model mice | |
| Concentrations | 1 mg/kg | |
| Incubation Time | 7, 14 or 21 days | |
| Results | These results suggest that the resistance to the c-Met and Hh inhibitor is developed following a prolonged treatment of each individual inhibitor; however, the resistance may be overcome by combining both c-Met and Hh inhibitors. |
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Source | Mol Cancer Ther (2017). Figure 1. INCB28060 (Abmole Bioscience. Houston, TX, USA) |
| Method | oral gavage | |
| Cell Lines | KPC and orthotopic transplant model mice | |
| Concentrations | 1 mg/kg | |
| Incubation Time | 7, 14 or 21 days | |
| Results | The data suggest that combination of both inhibitors with gemcitabine shows a trend in shrinkage of primary tumor volume in both mouse models of PDA after one week of treatment regimen. |
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Source | Can Res (2017). Figure 3.INC280 (Abmole Bioscience). |
| Method | ||
| Cell Lines | PDAC cells | |
| Concentrations | ||
| Incubation Time | ||
| Results | As expected, neither the Hh inhibitor nor the HGF/c-Met inhibitor affected the levels of total AnxA2 or P-Y23-AnxA2 in Panc10.05 cells in the singly cultured serum-reduced media (Fig. 3A and B; Supplementary Fig. S5E and S5F). It is likely the concentration of HGFand IGF-1 in serum-reduced media is lower than the effective thresholds. |
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Source | Nature (2015). Figure 3. PF-04217903 and INCB28060 (AbMole Bioscience) |
| Method | mice treatment in vivo and histological evaluation | |
| Cell Lines | B16F10 cells | |
| Concentrations | 40mg/kg PF-04217903 and 50mg/kg INCB28060 | |
| Incubation Time | 2 weeks | |
| Results | Systemic treatment of WT mice carrying B16F10 melanomas (which are dependent on MET14) with three different MET tyrosine-kinase inhibitors (PF-04217903, INCB28060 and JNJ-38877605), strongly reduced TAN recruitment . |
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Source | Nature (2015). Figure 2. PF-04217903 and INCB28060 (AbMole Bioscience) |
| Method | mice treatment in vivo and histological evaluation | |
| Cell Lines | B16F10 cells | |
| Concentrations | 40mg/kg PF-04217903 | |
| Incubation Time | 2 weeks | |
| Results | "Systemic administration of PF-04217903 decreased the weight and volume of B16F10 melanomas by 36% and 54%, respectively. Instead, MET knockdown in cancer cells only, led to 58% and 75% inhibition of tumour growth and volume.TAN inhibition by PF-04217903 was comparable in both Met-silenced and scrambled B16F10 melanomas." |
| Cell Experiment | |
|---|---|
| Cell lines | SUN-5 and SUN-1 cells |
| Preparation method | Optimal cell density used in the viability assay was predetermined for individual cell lines. To determine compound potency, cells were seeded into 96-well microplates at the appropriate density in media containing 1% to 2% FBS and supplemented with serial dilutions of INCB28060 in a final volume of 100 μL per well. After 72-hour incubation, 24 μL of CellTiter 96 AQueous One Solution (Promega) was added to each well, and the plates were incubated for 2 hours in a 37°C incubator. The optical density was measured in the linear range using a microplate reader at 490 nm with wavelength correction at 650 nm. IC50 values were calculated using the GraphPad Prism Software. |
| Concentrations | 0~333 nM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | B16F10 tumour-bearing mice |
| Formulation | 0.5% methylcellulose in saline |
| Dosages | 50mg/kg INCB28060 |
| Administration | via oral gavage every day once a day starting from day 2 after tumour injection and twice a day from day 11 until the end of the experiment(2 weeks) |
| Molecular Weight | 412.42 |
| Formula | C23H17FN6O |
| CAS Number | 1029712-80-8 |
| Solubility (25°C) | DMSO 15 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.
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Capmatinib dihydrochloride hydrate is a potent, orally active, selective, ATP-competitive c-Met kinase inhibitor (IC50=0.13 nM) that inhibits the phosphorylation of c-MET, as well as downstream effector proteins of the c-MET pathway, such as ERK1/2, AKT, FAK, In addition, Capmatinib dihydrochloride hydrate effectively inhibited the proliferation and migration of c-Met-dependent tumor cells, induced apoptosis, and demonstrated antitumor activity in a mouse model of tumor. Capmatinib dihydrochloride hydrate is mainly metabolized by CYP3A4 and aldehyde oxidase. |
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