NVP-BVU972

NVP-BVU972 is a selective and potent MET kinase inhibitor with an IC50 of 14 nM. NVP-BVU972 potently inhibits MET kinase but displays low inhibition against other kinases including the most closely related kinase RON with IC50 values of more than 1000 nM. NVP-BVU972 also suppresses constitutive MET phosphorylation in GTL-16 cells or HGF-stimulated MET phosphorylation in A549 cells with IC50 values of 7.3 and 22 nM, respectively. NVP-BVU972 potently prevents the growth of the MET gene amplified cell linse GTL-16, MKN-45 and EBC-1 with IC50 values of 66, 82 and 32 nM, respectively. In good agreement with their high frequency in the NVP-BVU972 screen, Y1230 and D1228 mutations causes dramatic shifts in the measured IC50 values for NVP-BVU972 in BaF3 cell line. Resistance triggered by V1155L is more limited to NVP-BVU972.A dose-dependent reduction in TPR-MET phosphorylation when applying NVP-BVU972 to BaF3 cells expressing wild-type TPR-MET. Both Y1230H and D1228A mutations abrogated the effect of NVP-BVU972 but not AMG 458. However, F1200I and L1195V interferes with the potency of NVP-BVU972 to prevent TPR-MET phosphorylation.