Optimized Plk1 PBD Inhibitors Based on Poloxin Induce Mitotic Arrest and Apoptosis in Tumor Cells.
Polo-like kinase 1 (Plk1) is a central regulator of mitosis and has been validated as a target for antitumor therapy. The polo-box domain (PBD) of Plk1 regulates its kinase activity and mediates the subcellular localization of Plk1 and its interactions with a subset of its substrates. Functional inhibition of the Plk1 PBD by low-molecular weight inhibitors has been shown to represent a viable strategy by which to inhibit the enzyme, while avoiding selectivity issues caused by the conserved nature of the ATP binding site. Here, we report structure-activity relationships and mechanistic analysis for the first reported Plk1 PBD inhibitor, Poloxin. We present the identification of the optimized analog Poloxin-2, displaying significantly improved potency and selectivity over Poloxin. Poloxin-2 induces mitotic arrest and apoptosis in cultured human tumor cells at low micromolar concentrations, highlighting it as a valuable tool compound for exploring the function of the Plk1 PBD in living cells.
Institute of Organic Chemistry, University of Leipzig , Johannisallee 29, 04103 Leipzig, Germany.
Andrej
A
Scharow
Johann Wolfgang Goethe-University , Medical School, Department of Gynecology and Obstetrics, Theodor-Stern-Kai 7-9, 60596 Frankfurt, Germany.
Monika
M
Raab
Johann Wolfgang Goethe-University Frankfurt , Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Max-von-Laue-Str. 7, 60438 Frankfurt, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Krishna
K
Saxena
Johann Wolfgang Goethe-University Frankfurt , Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Max-von-Laue-Str. 7, 60438 Frankfurt, Germany.
Sridhar
S
Sreeramulu
Johann Wolfgang Goethe-University Frankfurt , Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Max-von-Laue-Str. 7, 60438 Frankfurt, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Denis
D
Kudlinzki
Johann Wolfgang Goethe-University Frankfurt , Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Max-von-Laue-Str. 7, 60438 Frankfurt, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Santosh
S
Gande
Johann Wolfgang Goethe-University , Medical School, Department of Gynecology and Obstetrics, Theodor-Stern-Kai 7-9, 60596 Frankfurt, Germany.
Christina
C
Dötsch
Johann Wolfgang Goethe-University , Medical School, Department of Gynecology and Obstetrics, Theodor-Stern-Kai 7-9, 60596 Frankfurt, Germany.
Elisabeth
E
Kurunci-Csacsko
Technische Universität München , Emil Erlenmeyer Forum 5, 85354 Freising, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Susan
S
Klaeger
Technische Universität München , Emil Erlenmeyer Forum 5, 85354 Freising, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Bernhard
B
Kuster
Johann Wolfgang Goethe-University Frankfurt , Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Max-von-Laue-Str. 7, 60438 Frankfurt, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Harald
H
Schwalbe
Johann Wolfgang Goethe-University , Medical School, Department of Gynecology and Obstetrics, Theodor-Stern-Kai 7-9, 60596 Frankfurt, Germany.|German Cancer Consortium (DKTK) , Heidelberg, Germany.
Klaus
K
Strebhardt
Institute of Organic Chemistry, University of Leipzig , Johannisallee 29, 04103 Leipzig, Germany.
Thorsten
T
Berg
D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000145:classification; D045744:Cell Line, Tumor; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000145:classification; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000145:classification; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
D001565:Benzoates; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011809:Quinones; D054852:Small Molecule Libraries; D000097869:Polo-Like Kinase 1; C569433:poloxin