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.
Highlights
Mitosis has been a target of anticancer therapies for decades
Virtual screening was conducted using Almond and Brutus [20,21,22], field-based molecular alignment, and virtual screening tools that take into account both steric and electrostatic features of the molecules
Compounds having similar backbone structures as rigosertib were omitted from the hit list
Summary
The earliest mitosis-perturbing drugs were antitubulin agents such as taxanes and vinca alkaloids, and their derivatives [1, 2]. These drugs inhibit microtubule assembly or disassembly dynamics by targeting tubulin subunits, the building blocks of microtubules. Microtubules undergo major rearrangements during mitosis: within a Authors' Affiliations: 1VTT Health, VTT Technical Research Centre of Finland; 2Centre for Biotechnology and 3Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku; 4Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery; 5School of Pharmacy, University of Eastern Finland, Kuopio, Finland; and 6Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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