title: Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules.
abstract: Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development.
authors.affiliation: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
authors.forename: Iliana A
authors.initials: IA
authors.lastname: Kesisova
authors.forename: Konstantinos C
authors.initials: KC
authors.lastname: Nakos
authors.forename: Avgi
authors.initials: A
authors.lastname: Tsolou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Angelis
authors.forename: Joe
authors.initials: J
authors.lastname: Lewis
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Chatzaki
authors.forename: Bogos
authors.initials: B
authors.lastname: Agianian
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
authors.forename: Maria D
authors.initials: MD
authors.lastname: Koffa
mesh_terms: D064127:Aurora Kinases; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D021381:Protein Transport / Q000187:drug effects
chemical_list: D006873:Hydroquinones; D007211:Indoles; C583421:OXVW5 compound; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases