title: BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo.
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.
authors.affiliation: Boehringer Ingelheim Austria GmbH, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Steegmaier
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Anke
authors.initials: A
authors.lastname: Baum
authors.forename: Péter
authors.initials: P
authors.lastname: Lénárt
authors.forename: Mark
authors.initials: M
authors.lastname: Petronczki
authors.forename: Martin
authors.initials: M
authors.lastname: Krssák
authors.forename: Ulrich
authors.initials: U
authors.lastname: Gürtler
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.forename: Simone
authors.initials: S
authors.lastname: Lieb
authors.forename: Jens
authors.initials: J
authors.lastname: Quant
authors.forename: Matthias
authors.initials: M
authors.lastname: Grauert
authors.forename: Günther R
authors.initials: GR
authors.lastname: Adolf
authors.forename: Norbert
authors.initials: N
authors.lastname: Kraut
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Peters
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Rettig
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011621:Pteridines / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D013050:Spectrometry, Fluorescence; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536