General description
A cell-permeable triazolopyridazine compound that acts as a potent, ATP-competitive (Ki = 2.7 & 23 nM using non-phosphorylated and phosphorylated MET kinase domain, respectively), and highly selective inhibitor against the tyrosine kinase activity of the HGF (hepatocyte growth factor) receptor c-MET (IC50 = 4 nM), while exhibiting little or no activity toward a panel of more than 210 other kinases, including the closely related RTK RON. Shown to inhibit the constitutive (IC50 = 40 nM in GTL16 cells) as well as HGF-stimulated (IC50 = 12 nM in A549 cells) MET autophosphorylation/activation in cultures in vitro and effectively suppress MET-dependent tumor growths in mice in vivo (twice daily oral dosings at 30 mg/kg). X-ray crystallography reveals that SGX523 locks MET in a "DFG-in" conformation with the triazolopyridazine moiety interacting with the hydrophobic side chains of Met1229 and Tyr1248, while Tyr1248 mutations are found to render MET insensitive to SGX523 inhibition both in cell-free and cell-based assays.
Packaging
Packaged under inert gas
Preparation Note
Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months -20°C.
Other Notes
Buchanan, S.G., et al. 2009. Mol. Cancer Ther.8, 3181.
Eder, J.P., et al. 2009. Clin. Cancer Res.15, 2207.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
Disclaimer
Toxicity: Regulatory Review (Z)
| Quality Segment | 100 |
| assay | ≥97% (HPLC) |
| form | powder |
| manufacturer/tradename | Calbiochem® |
| storage condition | OK to freeze,protect from light |
| color | tan |
| solubility | DMSO: 2.5 mg/mL |
| shipped in | ambient |
| storage temp. | −20°C |
| SMILES string | S(c3[n]4c(nn3)C=CC(=N4)c5c[n](nc5)C)c1cc2c(nccc2)cc1 |
| InChI | 1S/C18H13N7S/c1-24-11-13(10-20-24)16-6-7-17-21-22-18(25(17)23-16)26-14-4-5-15-12(9-14)3-2-8-19-15/h2-11H,1H3 |
| InChI key | BCZUAADEACICHN-UHFFFAOYSA-N |
