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

Jenni Mäki-Jouppila, Leena Laine, Jonathan Rehnberg, Elli Narvi, Pekka Tiikkainen, Elvira Hukasova, Pasi Halonen, Arne Lindqvist, Lila Kallio, Antti Poso, Marko Kallio (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

5 Citations (Scopus)

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 compoundsmodulated 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 effectswhen added to cells during mitosis. Analysis of Plk1 activity in cells using a Forster 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.
Original languageEnglish
Pages (from-to)1054-1066
JournalMolecular Cancer Therapeutics
Volume13
Issue number5
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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    Mäki-Jouppila, J., Laine, L., Rehnberg, J., Narvi, E., Tiikkainen, P., Hukasova, E., Halonen, P., Lindqvist, A., Kallio, L., Poso, A., & Kallio, M. (2014). Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. Molecular Cancer Therapeutics, 13(5), 1054-1066. https://doi.org/10.1158/1535-7163.MCT-13-0685