title: Plk1-targeted small molecule inhibitors: molecular basis for their potency and specificity.
abstract: Members of polo-like kinases (collectively, Plks) have been identified in various eukaryotic organisms and play pivotal roles in cell proliferation. They are characterized by the presence of a distinct region of homology in the C-terminal noncatalytic domain, called polo-box domain (PBD). Among them, Plk1 and its functional homologs in other organisms have been best characterized because of its strong association with tumorigenesis. Plk1 is overexpressed in a wide spectrum of cancers in humans, and is thought to be an attractive anti-cancer drug target. Plk1 offers, within one molecule, two functionally different drug targets with distinct properties-the N-terminal catalytic domain and the C-terminal PBD essential for targeting the catalytic activity of Plk1 to specific subcellular locations. In this review, we focused on discussing the recent development of small-molecule and phosphopeptide inhibitors for their potency and specificity against Plk1. Our effort in understanding the binding mode of various inhibitors to Plk1 PBD are also presented.
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang 363-883, Korea.
authors.forename: Ravichandran N
authors.initials: RN
authors.lastname: Murugan
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
authors.forename: Chaejoon
authors.initials: C
authors.lastname: Cheong
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Bang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000032:analysis / Q000737:chemistry / Q000627:therapeutic use; D013379:Substrate Specificity; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D000097869:Polo-Like Kinase 1