PF-04217903 (PF-4217903) is a novel ATP-competitive small molecule inhibitor of c-Met kinases with the IC50 values from 3.1 nM to 142 nM. PF-04217903 (PF-4217903) demonstrated >1000 fold selectivity for c-Met compared with >150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 (PF-4217903) inhibited tumor cell proliferation, survival, migration/invasion in MET amplified cell lines in vitro, and demonstrated marked antitumor activity in tumor models harboring either MET gene amplification or a HGF/c-Met autocrine loop at well-tolerated dose levels in vivo.
Pharmacol Res. 2023 Jan 7;188:106640.
Blocking the HGF-MET Pathway Induces Resolution of Neutrophilic Inflammation by Promoting Neutrophil Apoptosis and Efferocytosis
PF-04217903 purchased from AbMole
Elife. 2019 Sep 19;8. pii: e47460.
A distinct cardiopharyngeal mesoderm genetic hierarchy establishes antero-posterior patterning of esophagus striated muscle.
PF-04217903 purchased from AbMole
Nature. 2015 Jun 18;522(7556):349-53.
MET is required for the recruitment of anti-tumoural neutrophils.
PF-04217903 purchased from AbMole
-2[1].jpg) |
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 . |
-1.jpg) |
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 | B16F1, Tib6, EL4, and LLC, and endothelial cells, HUVECs and C166 |
| Preparation method | Cell lines, including B16F1, Tib6, EL4, and LLC, and endothelial cells, HUVECs and C166, were seeded at 104 cells in each well of 24-well tissue culture–treated plates. Cells were grown in the standard media as described earlier. Cells were treated with different concentrations (2, 0.2, and 0.02 μmol/L) of sunitinib, PF-04217903, and combination of both compounds for 4 days. Efficacy of the compounds was measured by counting cells in a Coulter counter machine (BD Biosciences). Similar approach was applied to evaluate the role of HGF or VEGF on cell proliferation, using 3 different concentrations (10, 100, and 200 ng/mL) of each ligand. |
| Concentrations | 2, 0.2, and 0.02 μmol/L |
| Incubation time | 4 days |
| Animal Experiment | |
|---|---|
| Animal models | B16F10 tumour-bearing mice |
| Formulation | 0.5% methylcellulose in saline |
| Dosages | 40mg/kg PF-04217903 |
| Administration | oral |
| Molecular Weight | 372.38 |
| Formula | C19H16N8O |
| CAS Number | 956905-27-4 |
| 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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