Receptor tyrosine kinases (RTKs) has been implicated in the development and progression of many types of cancer. The hepatocyte growth factor (HGF) RTK, as known as MET, is required for various morphogenetic events in both embryonic and adult organisms. c-Met is a receptor-type tyrosine kinase, which is involved in a wide range of cellular responses such as proliferation, motility, migration and invasion. c-MET RTK and its ligand, hepatocyte growth factor (HGF), exist in most solid tumors and c-MET signaling has been documented in a wide range of human malignancies[3]. NVP-BVU972 is a novel selective c-MET kinase inhibitor with an IC 50 of 14 nM which better than 10 μM in kinase RON. Cell lines were seeded with viral supernatants for 14 to 16h in the presence of 6 μg/mL polybrene and cell lines replaced with growth medium subsequently to obtain cell lysates for protein expression levels and activation status of Met. The result showed that NVP-BVU972 potently prevents the growth of the MET gene amplified cell lines GTL-16, MKN-45 and EBC-1 with IC50 values of 66 nM, 82 nM and 32 nM, respectively, which indicate that NVP-BVU972 possessed great sensitivity to MET. Moreover, after BaF3 cell line was induced with N-ethyl-N-nitrosourea (ENU) for 16h, NVP-BVU972 was added to a final concentration of 600, 1,200, 2,400, 4,800, or 9,600 nM, suggesting that Y1230 and D1228 mutations give rise to both shifts to greater than 129 nM of the measured IC50 values[4].
作用机制
The π-stacking of the core imidazo-pyridazine moiety of NVP-BVU972 with the aromatic side chain of Y1230 binds to the c-MET kinase.
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