Human polo-like kinase 1 (PLK1) is essential during mitosis and in the maintenance of genomic stability. PLK1 is overexpressed in human tumours and has prognostic potential in cancer, indicating its involvement in carcinogenesis and its potential as a therapeutic target. The use of different PLK1 inhibitors has increased our knowledge of mitotic regulation and allowed us to assess their ability to suppress tumour growth in vivo. We address the structural features of the kinase domain and the unique polo-box domain of PLK1 that are most suited for drug development and discuss our current understanding of the therapeutic potential of PLK1.
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We thank Yves Matthess and Sven Kappel for their assistance with the diagrams in this manuscript.
The authors declare no competing financial interests.
National Cancer Institute
The chemical strategy that uses active site-directed probes to directly profile the functional state of enzyme families in complex proteomes.
- Centromere region
A specialized segment of the chromosome that is typically observed as a primary constriction that functions in sister chromatid adhesion, kinteochore formation and pairing of homologous chromosomes, and is involved in the control of gene expression.
A highly organized organelle that acts as the cell microtubule-organizing center and includes two centrioles that are surrounded by an amorphous, proteinaceous matrix termed the pericentriolar material.
- Chemical lead optimization programme
The purpose of this stage during the process of drug development is to optimize the molecules or compounds that demonstrate the potential to be transformed into drugs. The creation of hundreds, possibly thousands, of analogues, is aimed at, for example, improving the effectiveness, diminishing the toxicity or increasing the organism's absorption of the drug.
A degradation signal found in certain proteins.
The plasma concentration required for obtaining 50% of the maximum effect in vivo.
- Equatorial spindle midzone
During metaphase the chromosomes congregate at the cell equator between the two ends to which the spindle tapers. This plane marks the point at which the whole cell will divide when nuclear division is completed.
The concentration of compound required for 50% inhibition of growth in vitro.
The concentration of compound required for 50% inhibition of an enzyme in vitro. Generally, nanomolar or even picomolar values rather than micromolar values are desirable.
- Ki value
The value of Ki corresponds to the inhibitor concentration when half of the enzyme molecules bind an inhibitor molecule (half-saturation concentration).
A protein structure in eukaryotes that assembles on the centromere and joins the chromosome to microtubule polymers from the mitotic spindle during mitosis.
- Mitotic catastrophe
A specific type of apoptotic response that occurs during mitosis as a consequence of deregulated (or abnormal) mitotic processes, which is one of the principal antiproliferative effects of most anticancer agents.
- Mitotic index
The mitotic index is the fraction of cells in a microscope field that contain condensed chromosomes.
A radial array of microtubules that are nucleated from duplicated but unseparated centrosomes surrounded by a ring of chromosomes.
A decrease in circulating neutrophils in the peripheral blood. The absolute neutrophil count (ANC) defines neutropaenia.
- Oriented peptide libraries
The consensus sequence of optimal peptide substrates is determined by sequencing the mixture of products generated during a brief reaction with the kinase of interest Based on these results, a library of several million peptide substrates is generated and used for determining the substrate specificity of protein kinases.
The most obvious conserved structural features of PLKs, which regulate their subcellular localization and their catalytic activity.
This region helps to hold both polo-boxes in the correct orientation.
- Post-mitotic bridge
As a cleavage furrow forms in late anaphase and then ingresses, the microtubules of the central spindle are pushed in a bridge that tethers the two daughter cells, which is called the mid-body.
The separation between mother and daughter cell during cell division requires cytoplasmic division. This process is called cytokinesis in mammalian cells and septation in fungi.
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Strebhardt, K., Ullrich, A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer 6, 321–330 (2006). https://doi.org/10.1038/nrc1841
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