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Mol Cancer Ther. 2014 May;13(5):1054-66. doi: 10.1158/1535-7163.MCT-13-0685. Epub 2014 Apr 18.

Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na.

Author information

1
Authors' Affiliations: VTT Health, VTT Technical Research Centre of Finland; Centre for Biotechnology and Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku; Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery; School of Pharmacy, University of Eastern Finland, Kuopio, Finland; and Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Abstract

Mitosis is an attractive target for the development of new anticancer drugs. In a search for novel mitotic inhibitors, we virtually screened for low molecular weight compounds that would possess similar steric and electrostatic features, but different chemical structure than rigosertib (ON 01910.Na), a putative inhibitor of phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathways. Highest scoring hit compounds were tested in cell-based assays for their ability to induce mitotic arrest. We identified a novel acridinyl-acetohydrazide, here named as Centmitor-1 (Cent-1), that possesses highly similar molecular interaction field as rigosertib. In cells, Cent-1 phenocopied the cellular effects of rigosertib and caused mitotic arrest characterized by chromosome alignment defects, multipolar spindles, centrosome fragmentation, and activated spindle assembly checkpoint. We compared the effects of Cent-1 and rigosertib on microtubules and found that both compounds modulated microtubule plus-ends and reduced microtubule dynamics. Also, mitotic spindle forces were affected by the compounds as tension across sister kinetochores was reduced in mitotic cells. Our results showed that both Cent-1 and rigosertib target processes that occur during mitosis as they had immediate antimitotic effects when added to cells during mitosis. Analysis of Plk1 activity in cells using a Förster resonance energy transfer (FRET)-based assay indicated that neither compound affected the activity of the kinase. Taken together, these findings suggest that Cent-1 and rigosertib elicit their antimitotic effects by targeting mitotic processes without impairment of Plk1 kinase activity.

PMID:
24748653
DOI:
10.1158/1535-7163.MCT-13-0685
[Indexed for MEDLINE]
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