Background:

IC50:< 5 nM in enzymatic assays

AMG 337 is a MET inhibitor.

MET receptor with its ligand can promote cell survival, proliferation, and invasion. The activation of MET signaling is a common regulator of various human cancer types, and thus, inhibition of MET signaling is an promising therapeutic opportunity for the treatment of cancer.

In vitro: AMG 337 could effectively inhibit MET kinase activity, and AMG 337 also showed great selectivity for MET when tested against a panel of over 400 protein as well as lipid kinases. In addition, AMG 337 was found to inhibit HGF-dependent MET phosphorylation. Furthermore, AMG 337 could only affect the viability of two gastric cancer cell lines with amplification of the MET gene. The IC50 values of AMG 337 for the two sensitive cell lines was less than 50 nM, whereas over 10 μM in all other tested cell lines [1].

In vivo: In anima study, it was found that the oral administration of AMG 337 led to the dose-dependent anti-tumor efficacy in MET amplified gastric cancer xenograft models, which was quite consistent with the PD modulation of MET signaling [1].

Clinical trial: A phase 1 clinical study is currently investigating the safety, tolerability and PK of AMG 337 in patients with solid tumors [2].

参考文献:
[1] Paul E.  Hughes, et al. AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models. Cancer Res October 1, 2014 74; 728
[2] https://clinicaltrials. gov/ct2/show/NCT01253707 term=AMG+337&rank=1