title: OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases.
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.
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Ji
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Arnst
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Tipton
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Bekier
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: William R
authors.initials: WR
authors.lastname: Taylor
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Yen
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Song-Tao
authors.initials: ST
authors.lastname: Liu
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors; D002503:Centromere / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000502:physiology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D061986:MCF-7 Cells; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009287:Naphthyridines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C585656:1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone; D000906:Antibodies; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C484610:MELK protein, human; D064107:Aurora Kinase B; D017346:Protein Serine-Threonine Kinases