title: In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1.
abstract: Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G(2)-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G(2)-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3.
authors.affiliation: GlaxoSmithKline R & D, 5 Moore Drive, Research Triangle Park, NC 27709, USA. timothy.j.lansing@gsk.com
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lansing
authors.forename: Randy T
authors.initials: RT
authors.lastname: McConnell
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Spehar
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Knick
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hassler
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Noro
authors.forename: Masaaki
authors.initials: M
authors.lastname: Furuta
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Emmitte
authors.forename: Tona M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; D000097868:Polo-like Kinases
chemical_list: D000255:Adenosine Triphosphate; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C524135:5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-((2-(trifluoromethyl)benzyl)oxy)thiophene-2-carboxamide; C486256:PLK3 protein, human; D000097868:Polo-like Kinases