Members of the polo subfamily of protein kinases (Plks) play crucial roles in cell cycle regulation and cell proliferation. Among them, Plk1 has been studied most extensively because of its ability to promote oncogenic transformation represents a potential target for new anticancer therapeutics development. While classical Plk inhibitors are typically directed against the ATP-binding cleft, Plks also contain C-terminal polo-box domains (PBDs) that recognize phospho-Ser (pSer)/phospho-Thr (pThr)-containing motifs, and which provide alternative and potentially specific means of inhibiting Plk function. By examining a series PBD-binding phosphopeptides, we previously identified the 5-mer phosphopeptide �PLHSpT� as minimal sequence that specifically interacts with the Plk1 PBD with high affinity but not with the two closely-related Plk2 and Plk3 PBDs [Nat. Struct. Mol. Biol., 2009 , 16, 876]. Recently, we discovered a new class of non-canonical PBD-ligand interactions that take advantage of a previously occluded hydrophobic binding channel [Nat. Chem. Biol., 2011 , 7, 595]. We also devised synthetic methodologies that permit the facile synthesis of these high affinity constructs [J. Org. Chem., 2011 , in press, DOI: 10.1021/jo201599c]. Herein, we utilize these synthetic methodologies to conduct structure activity relationship (SAR) studies with a focus on developing pThr mimetics as a means to improve their drug-like properties, in particular, cell membrance permeability and proteolytic stability.

Structure-based development of biovailable polo-like kinase 1 (Plk1) polo-box domain-binding peptides

243rd National Meeting (2012)

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