American Association for Cancer Research
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Data Supplement from Centmitor-1, a Novel Acridinyl-Acetohydrazide, Possesses Similar Molecular Interaction Field and Antimitotic Cellular Phenotype as Rigosertib, ON 01910.Na

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posted on 2023-04-03, 14:04 authored by Jenni H.E. Mäki-Jouppila, Leena J. Laine, Jonathan Rehnberg, Elli Narvi, Pekka Tiikkainen, Elvira Hukasova, Pasi Halonen, Arne Lindqvist, Lila Kallio, Antti Poso, Marko J. Kallio

Supplemental Movie 5. Microtubule dynamicity in a control A549 cell stably expressing EGFP-alpha-tubulin. Cells were treated with DMSO for 1 h before the analysis of microtubule dynamicity using 10 s frame capture interval for a total of 4 min. For the analysis, microtubule plus-ends were marked (blue dots) and the total growth and shrinkage velocities of individual microtubules were measured.



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. Mol Cancer Ther; 13(5); 1054–66. ©2014 AACR.

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