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OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases
Wenbin Ji1, Christopher Arnst1, Aaron R Tipton1
1Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
Plos One
|April 16, 2016
Summary
OTSSP167, a MELK inhibitor in clinical trials, disrupts the mitotic checkpoint. This effect is not solely due to MELK inhibition but also off-target kinase activities, impacting cancer cell killing mechanisms.
Area of Science:
- Molecular and Cellular Oncology
- Cancer Therapeutics
- Cell Cycle Regulation
Background:
- Maternal embryonic leucine zipper kinase (MELK) is a target for cancer therapy, with OTSSP167 being a potent inhibitor.
- OTSSP167 is undergoing Phase I clinical trials for refractory solid tumors.
- Understanding the precise mechanisms of action of novel cancer therapeutics is crucial.
Purpose of the Study:
- To investigate the mechanism by which OTSSP167 abrogates the mitotic checkpoint.
- To determine if MELK inhibition is the sole cause of OTSSP167's cellular effects.
- To identify potential off-target activities of OTSSP167.
Main Methods:
- Cellular assays to assess mitotic checkpoint abrogation.
- RNA interference (RNAi) mediated silencing of MELK.
- In vitro and cellular kinase inhibition assays.
- Analysis of histone phosphorylation and protein complex localization.
Main Results:
- OTSSP167 abrogates the mitotic checkpoint at concentrations inhibiting MELK.
- MELK silencing alone does not recapitulate the observed mitotic checkpoint abrogation.
- OTSSP167 exhibits off-target inhibition of Aurora B kinase and also inhibits BUB1 and Haspin kinases.
- Inhibition of these kinases leads to reduced histone phosphorylation and mislocalization of Aurora B complex.
Conclusions:
- OTSSP167 possesses multiple mechanisms of action beyond MELK inhibition for cancer cell killing.
- Off-target kinase inhibition contributes significantly to OTSSP167's observed cellular effects.
- Caution is advised when using OTSSP167 as a specific MELK inhibitor in research assays.
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