Plk1-targeted small molecule inhibitors: molecular basis for their potency and specificity

Mol Cells. 2011 Sep;32(3):209-20. doi: 10.1007/s10059-011-0126-3. Epub 2011 Jul 29.

Abstract

Members of polo-like kinases (collectively, Plks) have been identified in various eukaryotic organisms and play pivotal roles in cell proliferation. They are characterized by the presence of a distinct region of homology in the C-terminal noncatalytic domain, called polo-box domain (PBD). Among them, Plk1 and its functional homologs in other organisms have been best characterized because of its strong association with tumorigenesis. Plk1 is overexpressed in a wide spectrum of cancers in humans, and is thought to be an attractive anti-cancer drug target. Plk1 offers, within one molecule, two functionally different drug targets with distinct properties-the N-terminal catalytic domain and the C-terminal PBD essential for targeting the catalytic activity of Plk1 to specific subcellular locations. In this review, we focused on discussing the recent development of small-molecule and phosphopeptide inhibitors for their potency and specificity against Plk1. Our effort in understanding the binding mode of various inhibitors to Plk1 PBD are also presented.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Catalytic Domain
  • Cell Cycle Proteins* / antagonists & inhibitors
  • Cell Cycle Proteins* / chemistry
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Drug Design
  • Gene Expression Regulation, Neoplastic / drug effects
  • High-Throughput Screening Assays
  • Humans
  • Models, Molecular
  • Molecular Targeted Therapy / methods*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases* / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases* / chemistry
  • Protein-Serine-Threonine Kinases* / genetics
  • Protein-Serine-Threonine Kinases* / metabolism
  • Proto-Oncogene Proteins* / antagonists & inhibitors
  • Proto-Oncogene Proteins* / chemistry
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism
  • Small Molecule Libraries / analysis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / therapeutic use
  • Substrate Specificity

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Small Molecule Libraries
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1