Abstract
Polo-like kinase 1 (Plk1) is an interesting molecule both as a biomarker and as a target for highly specific cancer therapy for several reasons. Firstly, it is over-expressed in many cancers and can serve as a biomarker to monitor treatment efficacy of Plk1 inhibitors. Furthermore, the Plk1 enzyme is expressed only in dividing cells and is a major regulator of the cell cycle. It controls entry into mitosis and regulates the spindle checkpoint. The expression of Plk1 in normal cells is not nearly as strong as that in cancer cells, which makes Plk1 a discriminating tartget for the development of cancer-specific small molecule drugs. RNA interference experiments in vitro and in vivo have indicated that downregulation of Plk1 expression represents an attractive concept for cancer therapy. Over the years, a number of Plk1 inhibitors have been discovered. Many of these inhibitors are substances that compete with ATP for the substrate binding site. The ATP-competitive inhibitor BI 6727 is currently being clinically tested in cancer patients. Another drug in development, poloxin, is the first Polo-box domain inhibitor of Plk1. This compound is a derivative of the natural product, thymoquinone, derived from Nigella sativa. A novel and promising strategy is to synthesize bifunctional inhibitors that combine the high binding affinity of ATP inhibitors with the specificity of competitive inhibitors.
Highlights
Polo-like kinase 1 (Plk1) plays a critical role in cell division and represents a promising target for cancer therapy
We focus on the biology of the Plk1 enzyme and the significance of small molecule inhibitors as novel candidates for cancer therapy
All Plks consist of an amino-terminal catalytic kinase domain, which is responsible for ATP-binding and enzyme activation, and a carboxy-terminal polo box domain (PBD)
Summary
Polo-like kinase 1 (Plk1) plays a critical role in cell division and represents a promising target for cancer therapy. To increase the specificity of Plk inhibition, substances binding to the PBD and competing with natural Plk substrates have been developed These compounds are able to block protein-protein interactions and consist of modified peptides, which contain consensus sequences for the corresponding substrates. The human proteome contains more than 2,000 different protein kinases of which Plk is just one [34] This illustrates the magnitude of the task of identifying a Plk specific inhibitor; finding a compound that only inhibits one particular kinase is quite difficult, especially when there are so many structurally similar enzymes present in the cell. GW843682X is a competitive ATP inhibitor, which occupies the ATP binding site and inhibits the kinase activity It arrested various cancer cell lines with aberrant Plk expression in the G2/M cell cycle phase and induced apoptosis. GW843682X revealed 400-fold greater inhibitory activity towards Plk than towards Plk and Plk3 [3]
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