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 Plk1-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 π-stacking interaction. This
π-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.