Polo-like kinase 1 as target for cancer therapy

Polo-like kinase 1 (Plk1) plays a critical role in cell division and represents a promising target for cancer therapy. Several small molecule inhibitors of polo-like kinase 1 have been described. In the present review, we focus on the biology of the Plk1 enzyme and the significance of small molecule inhibitors as novel candidates for cancer therapy. Polo-like kinases are serine-threonine protein kinases. There are four different polo-like kinases (Plk 1-4), of which Plk1 is the best studied. 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). The PBD is involved in phosphopeptide binding and consists of either one (in Plk 4) or two sequence motifs (in Plk 1, Plk 2, and Plk 3) which each consist of 80 residues [1]. Phosphopeptides bind to the two motif-PBDs at the consensus sequence S-pS/pT-P/X [2]. The PBDs of the four Plks are similar, but not identical and have different binding affinities. Plk1 and Plk 2 share the most similar PBDs, whereas Plk4’s PBD is most dissimilar. Because the Plk4 PBD consists of only one motif, it does not form a binding pocket as the other Plks do [1,3]. Plk1 consists of 603 amino acids [4].Plks possess a conserved catalytic kinase domain, which consists of two lobes, each composed of a polypeptide chain. A hinge region connects these two lobes allowing their rotation. ATP molecules can bind at the gap between the two polypeptide chains. The binding pocket structure is highly conserved among all Plks. In general, all protein kinases reveal similar ATP-binding pockets, which may pose problems in developing highly specific kinase inhibitors [1,3].Protein kinases are important for a multitude of cellular signal transduction reactions and are, therefore, subject to strong regulation. They can be activated or inactated by interaction with other proteins, peptides, or small molecules or by translocation in the cell. Protein kina