title: Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain.
abstract: Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
authors.affiliation: Leipzig University, Institute of Organic Chemistry, Johannisallee 29, 04103, Leipzig, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Scharow
authors.affiliation: Leipzig University, Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine (BBZ), Deutscher Platz 5, 04103, Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Knappe
authors.affiliation: Max Planck Institute of Biochemistry, Department of Molecular Biology, Am Klopferspitz 18, 82152, Martinsried, Germany.|Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419, Hamburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.affiliation: Leipzig University, Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine (BBZ), Deutscher Platz 5, 04103, Leipzig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hoffmann
authors.affiliation: Leipzig University, Institute of Organic Chemistry, Johannisallee 29, 04103, Leipzig, Germany. tberg@uni-leipzig.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005454:Fluorescence Polarization; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
keywords: bioorganic chemistry; inhibitors; peptides; protein kinases; protein-protein interactions