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  • Title: Design, synthesis and biological evaluation of phosphopeptides as Polo-like kinase 1 Polo-box domain inhibitors.
    Author: Lin TY, Min HP, Jiang C, Niu MM, Yan F, Xu LL, Di B.
    Journal: Bioorg Med Chem; 2018 Jul 23; 26(12):3429-3437. PubMed ID: 29807699.
    Abstract:
    Polo-like kinase 1 (Plk1) is an anti-cancer target due to its critical role in mitotic progression. A growing body of evidence has documented that Peptide-Plk1 inhibitors showed high Plk1 binding affinity. However, phosphopeptides-Plk1 inhibitors showed poor cell membranes permeability, which limits their clinical applications. In current study, nine candidate phosphopeptides consisting of non-natural amino acids were rationally designed and then successfully synthesized using an Fmoc-solid phase peptide synthesis (SPPS) strategy. Moreover, the binding affinities and selectivity were evaluated via fluorescence polarization (FP) assay. The results confirmed that the most promising phosphopeptide 6 bound to Plk1 PBD with the IC50 of 38.99 nM, which was approximately 600-fold selectivity over Plk3 PBD (IC50 = 25.44 μM) and nearly no binding to Plk2 PBD. Furthermore the intracellular activities and the cell membrane permeability of phosphopeptide 6 were evalutated. Phosphopeptide 6 demonstrated appropriate cell membrane permeability and arrested HeLa cells cycle in G2/M phase by regulating CyclinB1-CDK1. Further, phosphopeptide 6 showed typical apoptotic morphology and induced caspase-dependent apoptosis. In conclusion, we expect our discovery can provide new insights into the further optimization of Plk1 PBD inhibitors.
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