Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents

Abstract

Although significant levels of side effects are often associated with their use, microtubule-directed agents that primarily target fast-growing mitotic cells have been considered to be some of the most effective anti-cancer therapeutics. With the hope of developing new-generation anti-mitotic agents with reduced side effects and enhanced tumor specificity, researchers have targeted various proteins whose functions are critically required for mitotic progression. As one of the highly attractive mitotic targets, polo-like kinase 1 (Plk1) has been the subject of an extensive effort for anti-cancer drug discovery. To date, a variety of anti-Plk1 agents have been developed, and several of them are presently in clinical trials. Here, we will discuss the current status of generating anti-Plk1 agents as well as future strategies for designing and developing more efficacious anti-Plk1 therapeutics.

Keywords: Plk1; anti-Plk1 agents; anti-cancer therapeutics; anti-mitotic agents; mitotic targets; polo-like kinase 1.

Figure 1.. Schematic diagram of human polo-like kinase 1 (Plk1).

The numbers indicate the positions of the amino acid residues in human Plk1.

Figure 2.. The structures of polo-like kinase 1 (Plk1) catalytic domain inhibitors.

Only widely studied inhibitors are shown.

Figure 3.. The binding modes of ADP (left panel, PDB: 3D5W) and volasertib (right panel, PDB: 3FC2) to the catalytic domain of polo-like kinase 1 (Plk1).

Ligand-binding regions that are important for achieving kinase selectivity are shown as colored surfaces. Region I is located near the conserved Asp-Phe-Gly (DFG) motif, which is important in the design of certain allosteric inhibitors. Region II is near the hinge region, and region III is a relatively hydrophobic pocket below the adenine-binding site. Compared to Plk2 and Plk3, residues that are specific (green) or semi-specific (red) to Plk1 are labeled. Notably, the aryl-methoxy group in region II (near L132 of the hinge region) is used to produce moderate selectivity for Plk1 against other Plks .

Figure 4.. The structures of peptidomimetic and small molecule polo-box domain (PBD) inhibitors.

Figure 5.. The structural model of polo-box domain (PBD) in complex with 4j.

The X-ray cocrystal structure of the PBD + 4j complex (PDB: 3RQ7) shows a “Y-shaped” binding pocket composed of three discrete but interlinked binding modules—namely, a p-Thr/p-Ser-binding module (violet), a Pro-binding module (yellow), and a hydrophobic channel (green). Residues highlighted in red are specific to Plk1 PBD. Inhibitors designed to bind to more than one of the three binding modules could possess a superior binding specificity because of the specific requirement of the shape and geometrical arrangement of their binding moieties (see text for details).