Abstract
OTSSP167 was recently characterized as a potent inhibitor for maternal embryonic leucine zipper kinase (MELK) and is currently tested in Phase I clinical trials for solid tumors that have not responded to other treatment. Here we report that OTSSP167 abrogates the mitotic checkpoint at concentrations used to inhibit MELK. The abrogation is not recapitulated by RNAi mediated silencing of MELK in cells. Although OTSSP167 indeed inhibits MELK, it exhibits off-target activity against Aurora B kinase in vitro and in cells. Furthermore, OTSSP167 inhibits BUB1 and Haspin kinases, reducing phosphorylation at histones H2AT120 and H3T3 and causing mislocalization of Aurora B and associated chromosomal passenger complex from the centromere/kinetochore. The results suggest that OTSSP167 may have additional mechanisms of action for cancer cell killing and caution the use of OTSSP167 as a MELK specific kinase inhibitor in biochemical and cellular assays.
Highlights
Maternal embryonic leucine zipper kinase (MELK, called MRK38 or pEg3) is a serine/ threonine protein kinase that belongs to the AMP-activated kinase (AMPK) related kinase family [1,2,3,4,5] (S1 Fig)
We tested whether OTSSP167 could interfere with mitosis
The data presented here showed that OTSSP167 is a relatively potent inhibitor of Aurora B kinase but its dramatic impact on mitosis progression cannot be fully explained by Aurora B inhibition alone
Summary
Maternal embryonic leucine zipper kinase (MELK, called MRK38 or pEg3) is a serine/ threonine protein kinase that belongs to the AMP-activated kinase (AMPK) related kinase family [1,2,3,4,5] (S1 Fig). The protein level and kinase activity of MELK are cell cycle regulated and peak during prometaphase [6, 7]. MELK was suggested to regulate G2/M transition there is controversy whether it functions as a negative or positive regulator for the transition [8, 9]. We have found that MELK is co-transcribed with a group of 64 core centromere/kinetochore components, suggesting a role in mitosis [10]. MELK interacts with, phosphorylates and activates transcription factor FOXM1, which drives expression of multiple mitosis regulatory proteins [11]. MELK has been reported to act during cytokinesis in Xenopus early embryos [12] and in human cancer cells [13, 14]. Microarray profiling listed MELK as one of the top-ranking (#11) chromosomal
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