The human MET proto-oncogene encodes the MET kinase, also known as HGF receptor. The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. LY2801653 is designed as a potent, orally bioavailable c-Met inhibitor. The mean IC50 value of LY2801653 for inhibition of MET auto-phosphorylation in HGF-stimulated H460 cells was 35.2 ± 6.9 nM and the IC50 for MET auto-phosphorylation in S114 cells was 59.2 nM. LY2801653, in the concentration range of 0.01–10 μM, completely blocked the HGF-induced DU-145 cell scattering. LY2801653 also demonstrated potent anti-proliferative activity in cell lines with MET gene amplification (MKN45, Hs746T and H1993). MET target inhibition studies to assess activity of LY2801653 were undertaken in S114 xenograft tumors created through subcutaneous implantation of S114 cells, a murine cell line engineered to express both human MET and HGF. MET phosphorylation was inhibited by 98 % with a single dose of 50-mg/kg LY2801653 for 2 h. Furthermore, LY2801653 treatment inhibited MET phosphorylation with a composite TED50 (50 % target inhibition dose) of 1.2 mg/kg and a composite TED90 of 7.4 mg/kg [3].
作用机制
LY2801653 bound MET is in an inactive form with the activation loop DFG motif adopting a DFG-out conformation .
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