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

Curr Biol. 2007 Feb 20;17(4):316-22. doi: 10.1016/j.cub.2006.12.037. Epub 2007 Feb 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Body Weight
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • Magnetic Resonance Imaging
  • Mice
  • Microscopy, Fluorescence
  • Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Pteridines / metabolism
  • Pteridines / pharmacology*
  • Signal Transduction / physiology*
  • Spectrometry, Fluorescence
  • Xenograft Model Antitumor Assays

Substances

  • BI 2536
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Pteridines
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1