Synthesis and Biological Evaluation of Novel Eg5 Inhibitors

Sarli, Vasiliki; Huemmer, Stefan; Sunder-Plassmann, Nils; Mayer, Thomas; Giannis, Athanassios

doi:10.1002/cbic.200500168

Cited by 51 publications

(30 citation statements)

References 25 publications

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“…Small molecule inhibitors were used as follows: 2 mM or 5 mM thymidine (Sigma), 500 nM nocodazole (Sigma), 20 mM MG132 (Cayman), 100 mM roscovitine (Sigma), 10 or 50 mM RO-3306 (Santa Cruz) and 20 mM VS-83 (ref. 32).…”

Section: Methodsmentioning

confidence: 99%

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

et al. 2014

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Section: Methodsmentioning

confidence: 99%

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

et al. 2014

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“…For comparison, monoastral spindles were produced in control cells by treatment with VS-83, a smallmolecule inhibitor of Eg5 (Sarli et al, 2005). Although HURP-positive K-fibers could readily be seen in both VS-83 and TAL-treated cells at time zero ( Figure 4A, left), cold treatment for 20 min virtually abolished HURP staining in TAL-treated cells but not in VS-83 treated cells (Figure 4A, right).…”

Section: Tal Treatment Produces Mitotic Defects Expected For Plk1 Inhmentioning

confidence: 99%

Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis

Santamaría

Neef

Eberspächer

et al. 2007

MBoC

173

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Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis. INTRODUCTIONThe error-free segregation of chromosomes during cell division is necessary for the maintenance of correct ploidy and genomic integrity, and errors in cell division are presumed to lead to aneuploidy and cancer (Rajagopalan and Lengauer, 2004). To ensure that daughter cells receive the correct complement of chromosomes, two key events need to be coordinated. First, chromosomes must be equally segregated, a process that depends on the mitotic spindle. Second, cytokinesis, the process dividing the cell into two, must occur between the two sets of segregated chromosomes. Both of these processes require the activity of a key cell cycle regulator, the Polo-like kinase 1 (Plk1). Plks form a conserved subfamily of serine/threonine protein kinases. The first member to be identified was Polo in Drosophila melanogaster (Llamazares et al., 1991) and, subsequently, four Plk family members have been identified in mammals Barr et al., 2004).Plk1 contains an N-terminal kinase domain and a phosphopeptide-binding C-terminal regulatory polo-box domain (PBD; Leung et al., 2002;Elia et al., 2003b). In vertebrates Plk1 has been implicated in the activation of Cdk1-cyclin B upon entry into mitosis, centrosome maturation via the recruitment of the ␥-tubulin ring complex (␥-TuRC), spindle formation, sister chromatid separation by cohesin removal from the chromosome arms, promotion of anaphase onset through direct phosphorylation of the APC/C complex as well as the inhibition of the APC/C inhibitor Emi1, and finally, mitotic exit and cytokinesis (reviewed in Barr et al., 2004). Fitting with these diverse functions, Plk1 localizes to the centrosomes, spindle poles, and kinetochores in prophase and metaphase, the central spindle in anaphase, and the midbody during cytokinesis. These localizations require the function of the PBD (Jang et al., 2002;Seong et al., 2002) and priming-kinases to generate phosphorylated docking sites that are subsequently recog...

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“…It binds to KSP and causes both local and distal conformational changes that allow ATP binding, but prevent ADP release. The weak inhibitory activity of monastrol and its non -drug-like properties led to the synthesis of a series of second-generation derivatives with improved cellular potency and solubility (16,17). Moreover, several other inhibitors that exhibit great chemical diversity have now been reported including adociasulfate-2 (2, 18), terpendole E (3, 19), HR22C16 (4,20), CK0106023 (5, 21), dihydropyrazoles (6,22), S-trityl-L-cysteine (7, 23), dihydropyrroles (8,24), thiazoles (9,25), and many more ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications

Sarli

Giannis²

2008

Clinical Cancer Research

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129

108

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Kinesin spindle protein (KSP), a member of the kinesin superfamily of microtubule-based motors, plays a critical role in mitosis as it mediates centrosome separation and bipolar spindle assembly and maintenance. Inhibition of KSP function leads to cell cycle arrest at mitosis with the formation of monoastral microtubule arrays, and ultimately, to cell death. Several KSP inhibitors are currently being studied in clinical trials and provide new opportunities for the development of novel anticancer therapeutics alternative from the available microtubule targeting drugs.

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Synthesis and Biological Evaluation of Novel Eg5 Inhibitors

Cited by 51 publications

References 25 publications

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis

Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications

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