Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

Gilmartin, Aidan G.; Bleam, Maureen R.; Richter, Mark C.; Erskine, Symon G.; Kruger, Ryan G.; Madden, Lenore; Hassler, Daniel F.; Smith, Gary K.; Gontarek, Richard R.; Courtney, Mary P.; Sutton, David; Diamond, Melody; Jackson, Jeffrey R.; Laquerre, Sylvie

doi:10.1158/0008-5472.can-09-0945

Cited by 110 publications

(98 citation statements)

References 46 publications

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“…In contrast, accumulation of aberrant spindles was observed following treatment with TAK-960 at 10 or 30 nmol/L. At 100 nmol/L or more concentration, the appearance and distribution of phenotypes consisted of monopolar spindles with characteristic polo spindle morphology (15).…”

Section: Tak-960 Mechanism Of Actionmentioning

confidence: 87%

TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

Hikichi

Honda

Hikami

et al. 2012

Molecular Cancer Therapeutics

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Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. 7,8,is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G 2 -M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC 50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC 50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700-9. Ó2011 AACR.

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Section: Tak-960 Mechanism Of Actionmentioning

confidence: 87%

TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

Hikichi

Honda

Hikami

et al. 2012

Molecular Cancer Therapeutics

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“…Gilmartin et al found that GSK461364 caused lung carcinoma cells to arrest at prometaphase, and at lower concentrations, mitotic cells exhibited abnormal spindles and chromatins that could not be arranged on the equatorial plate. At higher concentrations, a monopolar spindle was formed and the chromatin decondensed around the monopolar spindle [25]. Another study reported that null-Plk1 led to the activation of SAC which was arrested at the prometaphase stage, thus showing developmental defects in zebrafish embryonic cells [2].…”

Section: Discussionmentioning

confidence: 99%

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

Zhang

Chen

Cui

et al. 2017

J Assist Reprod Genet

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Purpose This study was conducted to examine the dynamic distribution of polo-like 1 kinase (Plk1) and the possible role it plays in first mitotic division during early porcine embryo development. Methods Indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses were used to study the dynamic expression and subcellular localization of Plk1 protein in pig parthenogenetic embryos. Finally, a selective Plk1 inhibitor, GSK461364, was used to evaluate the potential role of Plk1 during this special stage.Results The results showed that Plk1 upon expression exhibited specific dynamic intracellular localization, which closely correlated with the α-tubulin distribution during the first mitotic division. GSK461364 treatment resulted in cleavage failure, with majority of the GSK461364-treated embryos being arrested in prometaphase. Further results of the subcellular structure examination showed that GSK461364 treatment led to a significantly higher proportion of the treated embryos having abnormal spindles and misarranged chromosomes at the prometaphase stage. Conclusions Thus, these results indicated that Plk1 is essential for porcine embryos to complete the first mitotic division. Furthermore, Plk1 regulation was associated with effects on spindle assembly and chromosome arrangement.

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“…[6][7][8] Several inhibitors of its catalytic activity are developed and some of them have proceeded to clinical trials. 9,10 We established a screening system for the inhibitors of PBD-dependent binding. 11 In this system, the open reading frame of a green fluorescent protein (GFP) is fused to PBD and expressed in bacteria.…”

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confidence: 99%

Trachyspic acid 19-butyl ester, a new inhibitor of Plk1 polo box domain-dependent recognition from uncharacterized fungus RKGS-F2684

et al. 2017

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Polo-like kinase 1 (Plk1) is a serine-threonine protein kinase that possesses many essential functions during mitosis and is one of the key regulators of mitotic cell division. 1,2 Although it has a catalytic domain of protein kinase at its N-terminus, it possesses a phosphopeptide binding domain named polo box domain (PBD) at its C-terminus. 3,4 PBD binds to other protein in a phosphorylation dependent manner. PBD-dependent binding not only is important for the subcellular localization, but is also necessary for the targeting of Plk1 to specific substrates. 3 Plk1 is frequently overexpressed in many cancers and inhibition of Plk1 by antisence oligonucleotides or small interfering RNA (siRNA) is highly effective in inhibiting cancer cell proliferation. The reduction of Plk1 is also shown to induce tumor regression in mouse xenograft model. 5 Thus, Plk1 is considered to be an attractive target for the treatment of human cancers. [6][7][8] Several inhibitors of its catalytic activity are developed and some of them have proceeded to clinical trials. 9,10 We established a screening system for the inhibitors of PBD-dependent binding. 11 In this system, the open reading frame of a green fluorescent protein (GFP) is fused to PBD and expressed in bacteria. Target phosphopeptides for the PBD binding sequence are chemically synthesized and bound covalently to maleimide-activated 96-well plates. The binding of GFP-PBD to the phosphopeptides was quantitated through spectrofluorometry. Using this system, we have obtained purpurogallin, a benzotropolone-containing natural compound from nutgalls as an inhibitor of PBD. 11 Several other inhibitors of PBD are also identified by other groups but currently no clinical trials have been reported. 12 We have developed a structure based compound isolation technique named NPPlot (Natural Products Plot), where secondary metabolites from microorganisms are analyzed by their MW and retention time on DAD-LC/MS. 13 These analytical data are accumulated and used for the spectral database establishment. Using the method, we have isolated several new metabolites with unprecedented skeletons from microbial sources, such as verticilactam, 14 spirotoamides, 15 pyrrolizilactone 16 and recently opantimycin A. 17 In the present study, we combined our high-throughput screening system for PBD inhibitors and the methodology of the fractionation of microbial metabolites with spectral database. Using these techniques, a new 5,5-spiroacetal metabolite, trachyspic acid 19-butyl ester (1) together with a known metabolite trachyspic acid (2) 18 with potent PBD inhibitory activity was isolated from uncharacterized fungus RKGS-F2684 (Figure 1). We report here the isolation, structure and biological activity of 1.In the course of screening from about 3000 microbial extracts using our high-throughput screening system, we found that the extracts from fungal strain RKGS-F2684, which was isolated from a soil sample collected in Kumamoto, Japan in 1995, contained potent inhibitory activity. An ethyl acetate sol...

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Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

Cited by 110 publications

References 46 publications

TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

Plk1 inhibition leads to a failure of mitotic division during the first mitotic division in pig embryos

Trachyspic acid 19-butyl ester, a new inhibitor of Plk1 polo box domain-dependent recognition from uncharacterized fungus RKGS-F2684

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