The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery
Inês Lima1, Fernanda Borges1, António Pombinho2
1CIQUP-IMS - Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre s/n, 4169-007 Porto, Portugal.
Abstract:
The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell's adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.
Insights
The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation. In cancer, targeting SAC kinases like Aurora B and MPS1 offers new anticancer strategies by overriding this checkpoint.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The spindle assembly checkpoint (SAC) is crucial for accurate chromosome segregation during cell division.
- SAC inactivation in cancer cells can lead to aneuploidy and cell death.
- Understanding SAC signaling is vital for developing targeted cancer therapies.
Purpose of the Study:
- To provide a concise overview of the spindle assembly checkpoint (SAC) signaling pathway.
- To review recent drug discovery strategies targeting SAC kinases for cancer treatment.
- To highlight novel anticancer agents designed to override SAC.
Main Methods:
- Literature review of SAC signaling mechanisms.
- Analysis of recent advancements in kinase inhibitor drug discovery.
- Focus on targeting Aurora B and monopolar spindle kinase (MPS1).
Main Results:
- SAC is a critical surveillance mechanism for mitotic fidelity.
- SAC inactivation in cancer cells can be a double-edged sword, leading to cell death.
- Targeting SAC kinases presents a promising avenue for novel anticancer drug development.
Conclusions:
- The SAC pathway is essential for preventing aneuploidy.
- Targeting specific kinases within the SAC pathway, such as Aurora B and MPS1, is a key strategy for developing new cancer therapeutics.
- Overriding SAC offers a potential approach to induce cell death in cancer cells.
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