AMG 458, a potent small molecule c-Met inhibitor, has significant anti-tumor activity in vivo

4976 c-Met is a receptor tyrosine kinase that signals through its ligand, hepatocyte growth factor (HGF), to mediate multiple biological activities including proliferation, survival, motility and migration. In cancer, HGF/c-Met signaling is often deregulated. Overexpression of c-Met occurs frequently in numerous types of tumors. Gene amplification and activating mutations leading to constitutive receptor activation have also been described in patient tumors. In addition, altered expression of this axis in several mouse models has implicated c-Met in tumorigenesis. Therefore, targeting c-Met has promise as an approach to treating patients with tumors harboring activated c-Met. AMG 458 was identified as a selective, orally bioavailable, ATP-competitive small molecule c-Met inhibitor. AMG 458 potently inhibited c-Met enzymatic activity with an IC 50 of 2 nM and blocked c-Met phosphorylation in PC3 cells with an IC 50 of 60 nM. AMG 458 inhibited signaling in a dose-dependent manner in vitro in NIH-3T3 cells stably expressing TPR-Met, a constitutively active form of c-Met. Consistent with its activity in vitro , AMG 458 significantly inhibited HGF-mediated c-Met phosphorylation in the mouse liver at 30 mg/kg PO (p 50 of 16 mg/kg and an associated plasma drug concentration (AUC 0-24 ) of 130 µM*h. Similarly, in the ligand-independent NIH 3T3/TPR-Met model, the ED 50 was 12 mg/kg with an associated plasma drug concentration (AUC 0-24 ) of 96 µM*h. Moreover, treatment with 100 mg/kg AMG 458 resulted in 100% inhibition of tumor growth and complete inhibition of c-Met phosphorylation for approximately 12 hours. Inhibition of c-Met activity in these tumors correlated with plasma drug concentration. Consistent with the inhibition of c-Met phosphorylation, proliferation was reduced and apoptosis was increased rapidly in tumors within 28 hours following a single dose. In summary, AMG 458 is a potent, orally bioavailable, selective inhibitor of c-Met that effectively blocks c-Met phosphorylation and demonstrates significant anti-tumor activity in animal models.