| Description: |
MLN8054 is a potent, selective and orally available aurora A kinase inhibitor with an IC50 of 4 nM. |
| Target: |
Aurora A:4 nM (IC50) |
| In Vivo: |
In the HCT-116 tumor-bearing mice, MLN8054 treatment inhibits tumor growth dose dependently. MLN8054 is generally well tolerated. MLN8054 also inhibits the growth of the PC-3 tumor xenograft in nude mice. MLN8054 Treatment Results in Inhibition of Aurora A, Accumulation of Mitotic Cells, and Apoptosis in vivo[1]. MLN8054 selectively inhibits Aurora A kinase activity when dosed at 30 mg/kg. At this dose in HCT116 tumor tissue, MLN8054 has been shown to inhibit Aurora A autophosphorylation, and induce an increase in the Aurora B substrate, pHisH3[2]. |
| In Vitro: |
MLN8054 is an ATP-competitive, reversible inhibitor of recombinant Aurora A kinase. MLN8054 is >40-fold more selective for Aurora A compared with the family member Aurora B. MLN8054 selectively inhibits Aurora A over Aurora B in cultured human tumor cells. MLN8054 treatment results in G2/M accumulation and spindle defects and inhibits proliferation in multiple cultured human tumor cells lines. MLN8054 effectively inhibits the growth of cells from diverse tissue origins with IC50 values ranging from 0.11 to 1.43 μM[1]. Treatment of human tumor cells grown in culture with MLN8054 shows a number of morphologic and biochemical changes associated with senescence[2]. |
| Cell Assay: |
MLN8054 is added to human tumor cells in 2-fold serial dilutions to achieve final concentrations ranging from 10 to 0.04 mM. MLN8054 at each dilution is added in triplicate with each replicate on a separate plate. Cells treated with DMSO (n=6 wells per plate; 0.2% final concentration) served as the untreated control. The cells are treated with MLN8054 for 96 h at 37°C in a humidified cell culture chamber. Cell viability in each cell line is measured by using the Cell Proliferation ELISA, BrdU colorimetric kit[1]. |
| Animal Administration: |
Mice: Nude mice bearing HCT-116 tumors are treated orally once per day for 21 consecutive days with either vehicle control or MLN8054 at doses of 3, 10, or 30 mg/kg. Tumor volumes are measured by using a vernier caliper and calculated[1]. |
| References: |
[1]. Manfredi MG, et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11.
[2]. Huck JJ, et al. MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol Cancer Res. 2010 Mar;8(3):373-84. |
