SU11274

(Z)-N-(3-chlorophenyl)-3-((3, 5-dimethyl-4-(1-methylpiperazine-4-carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxoindoline-5-sulfonamide

SU11274 is a selective Met inhibitor with IC50 of 10 nM.

SU11274 exhibits greater than 50-fold selectivity for Met versus Flk and more than 500 times selectivity versus other tyrosine kinases such as FGFR-1, c-src, PDGFbR, and EGFR. SU11274 inhibits the phosphorylation of key regulators of the PI3K pathway, including AKT, FKHR, or GSK3beta. SU11274 treatment inhibits the growth of TPR-MET-transformed BaF3 cells in a dose-dependent manner with IC50 of <3 uM in the absence of interleukin 3, without growth inhibition of BaF3 cells transformed by other oncogenic tyrosine kinases, including BCR-ABL, TEL-JAK2, TEL-ABL, and TEL-PDGFbetaR. In addition to cell growth, SU11274 treatment significantly inhibits the migration of BaF3. TPR-MET cells by 44.8% and 80% at 1 uM and 5 uM, respectively. SU11274 inhibits HGF-dependent phosphorylation of Met as well as HGF-dependent cell proliferation and motility with an IC50 of 1-1.5 uM. In H69 and H345 cells which have functional Met receptor, SU11274 inhibits the HGF-induced cell growth with IC50 of 3.4 uM and 6.5 uM, respectively. SU11274 induces G1 cell cycle arrest with cells in G1 phase increased from 42.4% to 70.6% at 5 uM, and induces caspase-dependent apoptosis by 24% at 1 uM. [2] SU11274 inhibits cell viability in c-Met-expressing non-small cell lung cancer (NSCLC) cells with IC50 values of 0.8-4.4 uM, and abrogates hepatocyte growth factor-induced phosphorylation of c-Met and its downstream signaling. [3]

In vitro Met kinase assay, 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 uM 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.

568, 09

Data independently produced by, , , Dr. Zhang of Tianjin Medical University, SU11274purchased from Selleck, Western blot analysis of c-Met, MAPK and Akt. 0-20M SU11724 was added.

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO