Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism
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HEK293 Cells
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HeLa Cells
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Peptides, Cyclic / chemical synthesis
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Peptides, Cyclic / metabolism
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Peptides, Cyclic / pharmacology*
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Peptidomimetics / chemical synthesis
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Peptidomimetics / metabolism
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Peptidomimetics / pharmacology*
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Polo-Like Kinase 1
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Protein Binding
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Protein Domains
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism
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Structure-Activity Relationship
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Zebrafish
Substances
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Cell Cycle Proteins
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Peptides, Cyclic
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Peptidomimetics
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases