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  BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo.

Steegmaier, M., Hoffmann, M., Baum, A., Lenart, P., Petronczki, M., Krššák, M., et al. (2007). BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Current Biology, 17(4), 316-322. doi:10.1016/j.cub.2006.12.037.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-1033-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-1037-E
Genre: Journal Article

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 Creators:
Steegmaier, M., Author
Hoffmann, M., Author
Baum, A., Author
Lenart, P.1, Author              
Petronczki, M., Author
Krššák, M., Author
Gürtler, U., Author
Garin-Chesa, P., Author
Lieb, S., Author
Quant, J., Author
Grauert, M., Author
Adolf, G. R., Author
Kraut, N., Author
lPeters, J. M., Author
Rettig, W. J., Author
Affiliations:
1Research Group of Cytoskeletal Dynamics in Oocytes, MPI for Biophysical Chemistry, Max Planck Society, ou_2640691              

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 Abstract: Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-molecule inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concentrations. The compound potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated intravenous dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochemistry and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers.

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Language(s): eng - English
 Dates: 2007-02-082007-02-20
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.cub.2006.12.037
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Title: Current Biology
Source Genre: Journal
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Pages: - Volume / Issue: 17 (4) Sequence Number: - Start / End Page: 316 - 322 Identifier: -