The overexpression and activation of the Met receptor and its ligand HGF (hepatocyte growth factor) are associated with a wide variety of human malignancies, as well as the tumor invasion. Capmatinib is a highly selective and potent c-Met inhibitor with IC50 values of 0.13nM (measured by recombinant kinase assays), without direct inhibitory effect on the RONβ, EGFR and HER-3. Cellular study showed a dose-dependent inhibition by Capmatinib against c-MET activation in both cells with constitutively active c-MET, such as SNU-5 (IC50=1.1nM) and S114 (IC50=0.9nM), and cells with HGF-stimulated c-MET, like A549 (IC50=0.7nM), U-87MG (IC50=1nM), 786-0 (IC50=0.6nM), H441 (IC50=0.7nM), H596 (IC50=0.4nM) and H1437 (IC50=0.3nM). Treatment with Capmatinib for 2h at concentration>0.98nM caused significant decreased p-c-MET, and its major downstream effectors, including phosphorylation of ERK1/2 (≥3.91nM), AKT (>0.98nM), FAK (≥3.91nM), GAB1(≥3.91nM), STAT3 (≥0.24nM)/5 (≥0.98nM), in SNU-5 with constitutively active c-MET. Consistent with this, Capmatinib suppressed growth of SNU-5 cells, with IC50 value of 1.2nM and a calculated IC90 value of 4.6nM, in c-Met-dependent manner. Significant apoptosis can be observed in SNU-5 cells treated with Capmatinib at concentration>5nM through DNA fragmentation and cleaved PARP. As prediction, Capmatinib dose-dependently prevented anchorage-independent U-87MG cell growth in soft agar and HGF-stimulated H441 cell migration at concentration ranging in 1-63nM. Though Capmatinib did not directly inhibit the other RTKs in kinase assays, the suppression of p-EGFR and p-HER3 by Capmatinib through cross talk in H1993 cells. Oral administration of Capmatinib at dose of 3, 10 and 30mg/kg for 2 weeks caused tumor growth inhibition dose-dependently in both mice xenograft S114 and U-87MG, with significant c-MET-phosphorylation in vivo[1].
作用机制
Capmatinib is an ATP-competitive c-MET inhibitor.[1]
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