title: Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na.
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.
authors.affiliation: 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.
authors.forename: Jenni H E
authors.initials: JH
authors.lastname: Mäki-Jouppila
authors.forename: Leena J
authors.initials: LJ
authors.lastname: Laine
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rehnberg
authors.forename: Elli
authors.initials: E
authors.lastname: Narvi
authors.forename: Pekka
authors.initials: P
authors.lastname: Tiikkainen
authors.forename: Elvira
authors.initials: E
authors.lastname: Hukasova
authors.forename: Pasi
authors.initials: P
authors.lastname: Halonen
authors.forename: Arne
authors.initials: A
authors.lastname: Lindqvist
authors.forename: Lila
authors.initials: L
authors.lastname: Kallio
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Marko J
authors.initials: MJ
authors.lastname: Kallio
mesh_terms: D054831:Acridones / Q000737:chemistry / Q000494:pharmacology*; D050256:Antimitotic Agents / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D018385:Centrosome / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D008970:Molecular Weight; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
chemical_list: D054831:Acridones; D050256:Antimitotic Agents; D018797:Cell Cycle Proteins; D005998:Glycine; D006834:Hydrazines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D000097869:Polo-Like Kinase 1; C000594115:N'-(3-bromo-4-hydroxybenzylidene)-2-(9-oxo-10(9H)-acridinyl)acetohydrazide; C507134:ON 01910