Cell lines

Human NSCLC H441 cell lines

Preparation method

The solubility of this compound in DMSO is >27.7mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0.01-10 μM, 2 h

Applications

In H441 cells, LY2801653 inhibited phosphorylation and downstream signaling of MET leading to a blockage of MET pathway. LY2801653 also inhibited proliferation, growth, migration and invasion of H441 cells.

Animal models

Six-week-old female severe combined immunodeficient (SCID) mice

Dosage form

Oral administration, 20 mg/kg

Application

LY2801653 inhibited growth of tumors, significantly inhibiting cells mitotic and angiogenesis. Treatment with LY2801653 reduced A549-luc-C8 tumor growth in SCID mice significantly comparing to control group and no change in body weight.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

LY2801653 is a potent and orally bioavailable inhibitor of c-MET kinase with IC50 value of 2 nM [1].

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 [1]. 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 [2].

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 [2].These observations demonstrated the LY2801653 was able to disrupt c-MET kinase downstream signaling via inhibiting the c-MET kinase activity.

Reference:
[1] Yan S B et al. , LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2012, 31: 833-844.