SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. SGX523, a novel, ATP-competitive kinase inhibitor remarkablefor its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.
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Source | Mol Cancer Ther (2009). Figure 3. SGX523 |
| Method | immunoblot | |
| Cell Lines | GTL16 cells | |
| Concentrations | 10 μmol/L | |
| Incubation Time | 1 h | |
| Results | In the gastric cancer cell line GTL16, MET gene amplification leads to constitutive signaling, which is abolished by SGX523 |
| Cell Experiment | |
|---|---|
| Cell lines | MDCK cells and A549 cells line (migration) |
| Preparation method | Scatter and Migration Assays To measure the effect of SGX523 on HGF-induced cell scatter, MDCK cells were plated at 1 × 103 per well in a 24-well plate and incubated at 37°C in 5% CO2 for 1 week in MEM and 10% fetal bovine serum. HGF (90 ng/mL) and various concentrations of SGX523 were added, and the cells were incubated for 18 h (37°C, 5% CO2 humidified incubator) and visualized. To investigate cell migration, A549 cells were plated in 12-well plates (6 × 104 per well) and incubated to confluence. A channel was introduced into the monolayers by scratching with a pipette tip. Various dilutions of compound were added in starve medium in the presence and absence of HGF (90 ng/mL). Twenty-four hours later, wells were checked for cell migration. Cells were stained and visualized as described. |
| Concentrations | 0, 0.04, 0.12, 0.36 and 3 μ M |
| Incubation time | 18h or 24h |
| Animal Experiment | |
|---|---|
| Animal models | Human GTL16 tumor xenografts in mice / U87MG tumor xenografts in mice |
| Formulation | 20% isopropanol, 200 mmol/L ammonium acetate, and 100 mmol/L Tris-HCl (pH 7.5); 25% (v/v) glycerol |
| Dosages | 10, 20, 30, and 100 mg/kg twice daily or 60 mg/kg daily starting at day 4 for 14 d / 10 or 60 mg/kg twice daily starting at day 5 for 22 d |
| Administration | oral gavage |
| Molecular Weight | 359.41 |
| Formula | C18H13N7S |
| CAS Number | 1022150-57-7 |
| Solubility (25°C) | DMSO 10 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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