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

Anna-Leena Salmela, Jeroen Pouwels, Jenni Mäki-Jouppila, Pekka Kohonen, Pauliina Toivonen, Lila Kallio, Marko Kallio (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

3 Citations (Scopus)

Abstract

Mitosis 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.
Original languageEnglish
Pages (from-to)436-445
JournalCarcinogenesis
Volume34
Issue number2
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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Aurora Kinases
M Phase Cell Cycle Checkpoints
Diamines
Cell Survival
Cell Division
Aurora Kinase B
Mitosis
Microtubules
Aurora Kinase A
Kinetochores
Spindle Apparatus
Polyploidy
Tubulin
Life Cycle Stages
Neoplasms
Chromosomes
pyrimidine
Pharmaceutical Preparations

Cite this

Salmela, A-L., Pouwels, J., Mäki-Jouppila, J., Kohonen, P., Toivonen, P., Kallio, L., & Kallio, M. (2013). Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases. Carcinogenesis, 34(2), 436-445. https://doi.org/10.1093/carcin/bgs339
Salmela, Anna-Leena ; Pouwels, Jeroen ; Mäki-Jouppila, Jenni ; Kohonen, Pekka ; Toivonen, Pauliina ; Kallio, Lila ; Kallio, Marko. / Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases. In: Carcinogenesis. 2013 ; Vol. 34, No. 2. pp. 436-445.
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abstract = "Mitosis 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.",
author = "Anna-Leena Salmela and Jeroen Pouwels and Jenni M{\"a}ki-Jouppila and Pekka Kohonen and Pauliina Toivonen and Lila Kallio and Marko Kallio",
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Salmela, A-L, Pouwels, J, Mäki-Jouppila, J, Kohonen, P, Toivonen, P, Kallio, L & Kallio, M 2013, 'Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases', Carcinogenesis, vol. 34, no. 2, pp. 436-445. https://doi.org/10.1093/carcin/bgs339

Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases. / Salmela, Anna-Leena; Pouwels, Jeroen; Mäki-Jouppila, Jenni; Kohonen, Pekka; Toivonen, Pauliina; Kallio, Lila; Kallio, Marko (Corresponding Author).

In: Carcinogenesis, Vol. 34, No. 2, 2013, p. 436-445.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Salmela, Anna-Leena

AU - Pouwels, Jeroen

AU - Mäki-Jouppila, Jenni

AU - Kohonen, Pekka

AU - Toivonen, Pauliina

AU - Kallio, Lila

AU - Kallio, Marko

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N2 - Mitosis 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.

AB - Mitosis 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.

U2 - 10.1093/carcin/bgs339

DO - 10.1093/carcin/bgs339

M3 - Article

VL - 34

SP - 436

EP - 445

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 2

ER -