论文演示

Results
• Induction of apoptosis by S39 in Hela cell line
Discussion
Previous studies revealed that Aurora kinases were expressed in mitosis as key regulators and were detected to be over expressing in a variety range of human tumors. We set up the HTS system to screen novel Aurora B inhibitors from a 70,000 compound library and found S39, a screened potent Aurora B lead compound with IC50 of 90.07 nM in the biochemical assay.
S39 is a novel potent inhibitor of Aurora B kinase with the IC50 90.07 nM in the biochemical assay in an ATP competitive manner.
Abstrate
S39 treatment on human tumor cells can inhibit the phosphorylation of Histone H3 (Ser10), a direct downstream substrate of Aurora B kinase, indicating S39 inhibits endogenous Aurora B kinase activity in cell-based level. Furthermore, S39 treatment blocks cell proliferation, inhibits colony formation and induces apoptosis in a wide range of human tumor cell lines. These results indicate that S39 is a potential lead compound to be an Aurora B inhibitor.
Discussion
We also compared the effect of S39 on the liver cancer cell line HepG2 and the normal liver cell line L-02, in which Aurora B’s expression is lower than HepG2. S39 can inhibit proliferation of HepG2 with the IC50 7.7 lM, while the IC50 of S39 on L-02is 51.2 lM. These findings suggest the potential of S39 as a promising antitumor agent with low toxicity and high safety. Further studies on the selectivity of S39 or its derivatives against other kinases are also in planning. The potential of S39 as a promising antitumor agent with low toxicity and high safety.It’s worthy of performing structure modification and in vivo study to further determine the therapeutic potential of this compound.
Here we describe a potent screened compound, S39, aiming to describe its new anti-cancer mechanism and develop a low-toxicity Aurora B inhibitor based on this lead compound.
Introduction
To date, many small molecule inhibitors of Aurora kinases have been developed, such as ZM447439, VX- 680, Hesperadin and AZD1152.
Although many of them target more than one Aurora kinase, all of these inhibitors show typical phenotypes as inhibition of Aurora B: inhibition of Histone H3 phosphorylation (Ser10), inhibition of cell proliferation and induction of apoptosis.
Introduction
The Aurora serine-threonine kinase family contains many essential regulators in mitosis and three highly conserved members have been identified in mammalians: Aurora A, B, and C (Carmena and Earnshaw 2003; Castro et al. 2002).
Among them, Aurora B is a chromosomal passenger protein.
Introduction
Inhibition of Aurora B’s activity can decrease Histone H3 phosphorylation on Ser10, induce wrong chromosome condensation and incomplete cytokinesis. Given the essential function of Aurora B in mitosis and association with tumorigenesis,inhibition of this kinase has been identified as a new approach to cancer therapy.
Discussion
Since it’s reported that the effects of lead compound in the cell-based assay are not consistent with the enzyme-based assay, such as off-target effect, we employed Western blotting and Immunofluorescence assay to detect the effect of S39 on endogenous Aurora B kinase activity. As a novel ATP competitive leader compound, S39 shows potent inhibition of Aurora B kinase activity in both of the biochemical kinase activity assay and in the cell-based assay.
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Flow cytometry analysis for apoptosis
StatistΒιβλιοθήκη cal analysisMaterials and methods
• Materials E. Coli Hela cell S39 • Methods Molecular docking Western blotting Immunofluorescence Cell viability and proliferation Flow cytometry analysis for apoptosis Colony formation
S39, a novel Aurora B kinase inhibitor, shows potent antineoplastic activity in human Hela cervical cancercell line
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Reporter:fangyuang
Abstrate
Aurora kinases, frequently detected to be overexpressing in human tumors, regulate many essential events during mitosis progression and have been regarded as potentially important targets for cancer therapy.
Introduction
Given the functions of Aurora kinases in human cancers and successful development of drugs, we had screened lead compounds targeting Aurora B from a library of small molecular compounds to search potential Aurora B inhibitors (Lang et al. 2010).