title: Peptide-based inhibitors of Plk1 polo-box domain containing mono-anionic phosphothreonine esters and their pivaloyloxymethyl prodrugs.
abstract: Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides may be used to disrupt PBD function, the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising in part from the di-anionic nature of the phosphoryl group. We report five-mer peptides containing mono-anionic pThr phosphoryl esters that exhibit single-digit nanomolar PBD binding affinities in extracellular assays and improved antimitotic efficacies in whole cell assays. The cellular efficacies of these peptides have been further enhanced by the application of bio-reversible pivaloyloxymethyl (POM) phosphoryl protection to a pThr-containing polypeptide. Our findings may redefine structural parameters for the development of PBD-binding peptides and peptide mimetics.
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Qian
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Dan
authors.initials: D
authors.lastname: Lim
authors.forename: Suk-Youl
authors.initials: SY
authors.lastname: Park
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004355:Drug Stability; D004952:Esters; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010769:Phosphothreonine / Q000737:chemistry*; D011355:Prodrugs / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004952:Esters; D010455:Peptides; D010769:Phosphothreonine; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1