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.
|Source||Mol Cancer Ther (2009). Figure 3. SGX523|
|Cell Lines||GTL16 cells|
|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 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 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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth.
Zhang YW, et al. Cancer Res. 2010 Sep 1;70(17):6880-90. PMID: 20643778.
Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications.
Diamond S, et al. Drug Metab Dispos. 2010 Aug;38(8):1277-85. PMID: 20421447.
SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.
Buchanan SG, et al. Mol Cancer Ther. 2009 Dec;8(12):3181-90. PMID: 19934279.
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