title: Design and synthesis of a cell-permeable, drug-like small molecule inhibitor targeting the polo-box domain of polo-like kinase 1.
abstract: BACKGROUND
  Polo-like kinase-1 (Plk1) plays a crucial role in cell proliferation and the inhibition of Plk1 has been considered as a potential target for specific inhibitory drugs in anti-cancer therapy. Several research groups have identified peptide-based inhibitors that target the polo-box domain (PBD) of Plk1 and bind to the protein with high affinity in in vitro assays. However, inadequate proteolytic resistance and cell permeability of the peptides hinder the development of these peptide-based inhibitors into novel therapeutic compounds.
  
  
  RESULTS
  In order to overcome the shortcomings of peptide-based inhibitors, we designed and synthesized small molecule inhibitors. Among these molecules, bg-34 exhibited a high binding affinity for Plk1-PBD and it could cross the cell membrane in its unmodified form. Furthermore, bg-34-dependent inhibition of Plk1-PBD was sufficient for inducing apoptosis in HeLa cells. Moreover, modeling studies performed on Plk1-PBD in complex with bg-34 revealed that bg-34 can interact effectively with Plk1-PBD.
  
  
  CONCLUSIONS
  We demonstrated that the molecule bg-34 is a potential drug candidate that exhibits anti-Plk1-PBD activity and possesses the favorable characteristics of high cell permeability and stability. We also determined that bg-34 induced apoptotic cell death by inhibiting Plk1-PBD in HeLa cells at the same concentration as PEGylated 4j peptide, which can inhibit Plk1-PBD activity 1000 times more effectively than bg-34 can in in vitro assays. This study may help to design and develop drug-like small molecule as Plk1-PBD inhibitor for better therapeutic activity.
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Ganipisetti
authors.initials: G
authors.lastname: Srinivasrao
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Sungmin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Mija
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Chaejoon
authors.initials: C
authors.lastname: Cheong
authors.affiliation: Institute for Innovative Cancer Research and Department of Convergence Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Ky-Youb
authors.initials: KY
authors.lastname: Nam
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Cheongju, Chung-Buk, Republic of Korea.
authors.forename: Pethaiah
authors.initials: P
authors.lastname: Gunasekaran
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Eunha
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Cheongju, Chung-Buk, Republic of Korea.
authors.forename: Nam-Hyung
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Bio-Materials, Graduate School and Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju, Republic of Korea.
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Ryu
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Bang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020134:Catalytic Domain; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D010755:Organophosphates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C000598272:bg-34 compound