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OTSSP167 Abrogates Mitotic Checkpoint through Inhibiting Multiple Mitotic Kinases.
Ji, Wenbin; Arnst, Christopher; Tipton, Aaron R; Bekier, Michael E; Taylor, William R; Yen, Tim J; Liu, Song-Tao.
Afiliación
  • Ji W; Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
  • Arnst C; Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
  • Tipton AR; Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
  • Bekier ME; Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
  • Taylor WR; Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
  • Yen TJ; Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
  • Liu ST; Department of Biological Sciences, University of Toledo, Toledo, Ohio, United States of America.
PLoS One ; 11(4): e0153518, 2016.
Article en En | MEDLINE | ID: mdl-27082996
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Puntos de Control de la Fase M del Ciclo Celular / Naftiridinas Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Puntos de Control de la Fase M del Ciclo Celular / Naftiridinas Límite: Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos