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

4 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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Antimitotic Agents
Phenotype
Mitosis
Microtubules
Phosphotransferases
M Phase Cell Cycle Checkpoints
Kinetochores
Centrosome
Fluorescence Resonance Energy Transfer
Spindle Apparatus
1-Phosphatidylinositol 4-Kinase
ON 01910
N'-(3-bromo-4-hydroxybenzylidene)-2-(9-oxo-10(9H)-acridinyl)acetohydrazide
Static Electricity
Chromosomes
Molecular Weight
Pharmaceutical Preparations

Cite this

Mäki-Jouppila, Jenni ; Laine, Leena ; Rehnberg, Jonathan ; Narvi, Elli ; Tiikkainen, Pekka ; Hukasova, Elvira ; Halonen, Pasi ; Lindqvist, Arne ; Kallio, Lila ; Poso, Antti ; Kallio, Marko. / Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 5. pp. 1054-1066.
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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.",
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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, vol. 13, no. 5, pp. 1054-1066. https://doi.org/10.1158/1535-7163.MCT-13-0685

Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. / Mäki-Jouppila, Jenni; Laine, Leena; Rehnberg, Jonathan; Narvi, Elli; Tiikkainen, Pekka; Hukasova, Elvira; Halonen, Pasi; Lindqvist, Arne; Kallio, Lila; Poso, Antti; Kallio, Marko (Corresponding Author).

In: Molecular Cancer Therapeutics, Vol. 13, No. 5, 2014, p. 1054-1066.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na

AU - Mäki-Jouppila, Jenni

AU - Laine, Leena

AU - Rehnberg, Jonathan

AU - Narvi, Elli

AU - Tiikkainen, Pekka

AU - Hukasova, Elvira

AU - Halonen, Pasi

AU - Lindqvist, Arne

AU - Kallio, Lila

AU - Poso, Antti

AU - Kallio, Marko

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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DO - 10.1158/1535-7163.MCT-13-0685

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