LY2801653

CEI-1407

LY2801653 is a potent, orally bioavailable, small-molecule inhibitor of c-MET kinase with a Ki value of 2 nM.

LY2801653 is a potent and orally bioavailable inhibitor of c-MET kinase with IC50 value of 2 nM. C-MET kinase is also known as hepacyte growth factor receptor (HGFR), which is a membrane-associated tyrosine kinase receptor. HGF is the only ligand for this receptor. The binding of HGF induces conformational changes of c-MET and thus activate tyrosine kinase activity, to process downstream signaling. C-MET signaling regulate various cellular functions including cell proliferation, survival and apoptosis, and abnormal activation of c-MET kinase may trigger tumor growth, angiogenesis and metastasis. Biochemical study and crystallization study identified LY2801653 was a potent ATP-competitive inhibitor of c-MET kinase, where the inhibition was completed by suppression of c-MET kinase phosphorylation. In vitro study showed that 0.01-10 μM LY2801653 was able to completely block HGF-induced DU-145 cell scattering regulated by c-MET kinase, which demonstrated the inhibition of c-MET kinase activity. When LY2801653 was screened with a panel of cell lines, it was found more potent anti-proliferative activity of LY2801653 in those cell lines with MET gene expression than without MET gene expression. Mice bearing U-87MG xenograft were treated with low dose (1.3 mg/kg) and high dose (12 mg/kg) LY2801653 once daily for 28 days, and the tissues were characterized. It was found that low dose treatment resulted in a trend of reducing the area of c-MET kinase-associated apoptosis while the high dose treatment resulted in significant reduced apoptosis area. Additionally, high dose resulted in the suppression of c-MET kinase-associated angiogenesis, and vessels tend to be normalized. These observations demonstrated the LY2801653 was able to disrupt c-MET kinase downstream signaling via inhibiting the c-MET kinase activity.

1206799-15-6

552.53

0.9987

Store at -20°C

LY-2801653; LY 2801653

MET

2 nM (Ki)

C30H22F2N6O3

N-[3-fluoro-4-[1-methyl-6-(1H-pyrazol-4-yl)indazol-5-yl]oxyphenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide

Soluble in DMSO

Evaluation sample solution: ship with blue ice. All other available size: ship with RT, or blue ice upon request