Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1

The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16e on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plkl-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts with Arg516 through a pi-stacking interaction. This pi-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h, a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a. Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.

Automated summary

This study successfully designed and synthesized a series of macrocyclic peptidomimetics with high selectivity and inhibitory activities against Plk1's PBD. Compound 16e showed more potent inhibitory activity than the previous PMQSpTPL. The pi-π stacking interaction between 16a and Arg516 revealed a new design strategy, and PEGylation of 16h caused delocalization and mitotic failure of Plk1. Furthermore, the number of phospho-H3-positive cells in zebrafish embryos correlated with the amount of 16a. These findings suggest that macrocyclic peptidomimetics can serve as valuable templates for potent and novel Plk1-PBD inhibitors.