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Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases

Kohonen P; Kallio M; Pouwels J; Maki-Jouppila J; Kallio L; Salmela AL; Toivonen P

dc.contributor.authorKohonen P
dc.contributor.authorKallio M
dc.contributor.authorPouwels J
dc.contributor.authorMaki-Jouppila J
dc.contributor.authorKallio L
dc.contributor.authorSalmela AL
dc.contributor.authorToivonen P
dc.date.accessioned2022-10-28T13:14:23Z
dc.date.available2022-10-28T13:14:23Z
dc.identifier.urihttps://www.utupub.fi/handle/10024/163818
dc.description.abstractMitosis represents a clinically important determination point in the life cycle of proliferating cells. One potential drug target within the mitotic machinery is the spindle assembly checkpoint (SAC), an evolutionarily conserved signaling pathway that monitors the connections between microtubules (MTs) and chromosomes. Mistakes in SAC signaling may lead to cell division errors that can trigger elimination of cancer cells at M phase or soon after exit from mitosis. In this study, we describe the cellular effects of a novel pyrimidine-2,4-diamine derivative that we discovered to inhibit the activity of SAC. The compound caused rapid escape from the mitotic arrest induced by lack of interkinetochore tension but not by lack of MT-kinetochore attachments. In cycling cells, the compound disrupted the architecture of mitotic spindle that triggered a transient M-phase arrest that was rapidly followed by a forced mitotic exit. The premature termination of M phase was found to be a consequence of precocious inactivation of SAC caused by a direct inhibitory effect of the compound on Aurora B kinase in vitro and in cells. The compound also targets Aurora A kinase and tubulin in vitro and in cells, which can explain the observed spindle anomalies. The reduced activity of Aurora B kinase resulted in polyploidy and suppression of cancer cell viability. Our data suggest that this new pharmacophore possesses interesting anticancer properties that could be exploited in development of mitosis-targeting therapies.
dc.language.isoen
dc.publisherOXFORD UNIV PRESS
dc.titleNovel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases
dc.identifier.urnURN:NBN:fi-fe2021042714545
dc.relation.volume34
dc.contributor.organizationfi=lääket. tdk yhteiset|en=Lääket. tdk yhteiset|
dc.contributor.organizationfi=PÄÄT Farmakologia lääkekehitys ja lääkehoito|en=PÄÄT Farmakologia lääkekehitys ja lääkehoito|
dc.contributor.organizationfi=mat.-luonn.t. tdk yhteiset|en=Mat.-luonn.t. tdk yhteiset|
dc.contributor.organizationfi=Turun biotiedekeskus|en=Turku Bioscience Centre|
dc.contributor.organization-code2606000
dc.contributor.organization-code2609201
dc.contributor.organization-code2607000
dc.contributor.organization-code2607102
dc.converis.publication-id2280138
dc.converis.urlhttps://research.utu.fi/converis/portal/Publication/2280138
dc.format.pagerange445
dc.format.pagerange436
dc.identifier.jour-issn0143-3334
dc.okm.affiliatedauthorKallio, Marko
dc.okm.affiliatedauthorPouwels, Jeroen
dc.okm.affiliatedauthorMäki-Jouppila, Jenni
dc.okm.affiliatedauthorSalmela, Anna-Leena
dc.okm.discipline1182 Biokemia, solu- ja molekyylibiologiafi_FI
dc.okm.discipline318 Lääketieteen bioteknologiafi_FI
dc.okm.discipline1182 Biochemistry, cell and molecular biologyen_GB
dc.okm.discipline318 Medical biotechnologyen_GB
dc.okm.internationalcopublicationnot an international co-publication
dc.okm.internationalityInternational publication
dc.okm.typeJournal article
dc.publisher.countryUnited Kingdomen_GB
dc.publisher.countryBritanniafi_FI
dc.publisher.country-codeGB
dc.relation.doi10.1093/carcin/bgs339
dc.relation.ispartofjournalCarcinogenesis
dc.relation.issue2
dc.year.issued2013


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