A potent, selective inhibitor of c-Met
SU11274 is a potent and selective inhibitor of Met kinase with IC50 value of 10nM [1].
SU11274 shows high selectivity toward Met kinase versus a serine/threonine kinase, cyclin-dependent kinase 2 (CDK2), or other receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor β (PDGFRβ) [1].
SU11274 ?has revealed to inhibit autophosphorylation of Met at kinase tyrosines 1234/1235 in NIH3T3 cells expressing drug-sensitive or drug-resistant MET mutants?and human lung cancer cell line H1993, however, concomitantly, increase total MET levels?dose-dependently. Cells treated with SU11274 (2?μM for 16?h)?has shown a reduction of Met Ubiquitination [2].
参考文献:
[1] Wang X1,?Le P,?Liang C,?Chan J,?Kiewlich D,?Miller T,?Harris D,?Sun L,?Rice A,?Vasile S,?Blake RA,?Howlett AR,?Patel N,?McMahon G,?Lipson KE. Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol Cancer Ther.?2003 Nov;2(11):1085-92.
[2] Leiser D1,?Pochon B1,?Blank-Liss W1,?Francica P1,?Glück AA1,?Aebersold DM1,?Zimmer Y1,?Medová M2. Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation. FEBS Lett.?2014 Mar 3;588(5):653-8.
Kinase experiment: | A chimeric protein is constructed containing the cytoplasmic domain of human c-Met fused to Glutathione S-transferase (GST) and expressed in SF9 cells. The c-Met kinase GST-fusion protein is used for an ELISA-based Met biochemical assay using the random copolymer poly(Glu:Tyr) (4:1) immobilized on microtiter plates as a substrate. IC50 value is determined with various concentrations of SU11274 in a buffer containing 5 μM ATP and 10 mM MnCl2, 50 mM HEPES (pH 7.5), 25 mM NaCl, 0.01% BSA, and 0.1 mM Na orthovanadate. The kinase reaction is performed for 5 minutes at room temperature. The extent of substrate phosphorylation is measured using horseradish peroxidase-conjugated anti-pTyr antibodies. |
Cell experiment: | Cells are exposed to various concentrations of SU11274 in the presence or absence of HGF for 24, 48, and 72 hours. The number of viable cells is determined using the MTT assay or trypan blue exclusion. Cell Cycle and apoptosis are measured by fluorescence-activated cell sorter analysis via propidium iodide staining and Annexin V-positive staining, respectively. |
参考文献: [1]. Wang X, et al. Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol Cancer Ther, 2003, 2(11):1085-1092. | |
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