Polo-like kinase 1 (Plk1) is a serine/threonine protein kinase that plays critical roles in cell cycle regulation. Because aberrant expression of this enzyme has been observed in various cancers, Plk1 has emerged as a clinically relevant target for the development of new anti-cancer agents.  Aside from a canonical ATP-dependent kinase domain, Plk1 also contains a C-terminal polo-box domain (PBD), which is responsible for allosteric regulation of the kinase domain through protein-protein interactions with phosphoserine (pSer) or phosphothreonine (pThr)-containing peptide sequences.  Our group has developed peptide mimetics containing “Ser-pThr” motifs that display low-nanomolar PBD-binding affinities. These compounds were designed to cause selective cytotoxicity in cancer cells that overexpress Plk1 by inhibiting proper localization of the enzyme and in so doing, result in disordered mitotic function. However, the constructs show decreased potency in cell-based assays, mainly due to poor membrane permeability and inactivation by cellular phosphatases. To address hydrolytic lability of the phosphoryl ester group, we have devised an efficient synthetic route to the phosphonate-based pThr mimetic, (2<i>S</i>,3<i>R</i>) 2-amino-3-methyl-4-phosphonobutanoic acid (Pmab), which also provides access to analogs having various substituents at the C3 position.  When incorporated into our peptidomimetic scaffold, several of the C3 analogs exhibit several-fold enhancements in binding affinity, while maintaining excellent binding selectivity for Plk1 versus the PBDs of Plks 2 and 3.  This work significantly advances the state of our current PBD-binding peptidomimetics, and it could be more broadly applicable for the investigation of structure-activity relationships of peptidomimetics targeted to other pThr-binding sites.

Phosphatase-stable peptidomimetic ligands of the polo-like kinase 1 polo-box domain

254th National Meeting (2017)

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