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PDBsum entry 2vgo
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References listed in PDB file
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Key reference
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Title
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Reversine, A novel aurora kinases inhibitor, Inhibits colony formation of human acute myeloid leukemia cells.
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Authors
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A.M.D'Alise,
G.Amabile,
M.Iovino,
F.P.Di giorgio,
M.Bartiromo,
F.Sessa,
F.Villa,
A.Musacchio,
R.Cortese.
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Ref.
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Mol Cancer Ther, 2008,
7,
1140-1149.
[DOI no: ]
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PubMed id
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Abstract
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The demonstration that the small synthetic molecule reversine
[2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of
committed cells into multipotent progenitor-type cells has raised hopes on the
exploitation of this small chemical tool for the generation of stem cells. Here,
we show that reversine causes a failure in cytokinesis and induces
polyploidization. These effects of reversine are due to the inhibition of Aurora
A and B, two related kinases that are implicated in several aspects of mitosis
and that are frequently amplified and overexpressed in human tumors. Reversine
inhibits the phosphorylation of histone H3, a direct downstream target of Aurora
kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently
entered phase II clinical trials for cancer treatment, reversine inhibited
colony formation of leukemic cells from patients with acute myeloid leukemia but
was significantly less toxic than VX-680 on cells from healthy donors. The
crystal structure of the reversine-Aurora B kinase complex shows that reversine
is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our
studies raise serious doubts on the application of reversine in regenerative
medicine, they support the paradigm that reversine might be a useful agent in
cancer chemotherapy.
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