Home » Key Drug Discovery Articles » Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP’s distribution on microtubules.

Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP’s distribution on microtubules.

Tripolin A, a novel small-molecule inhibitor of aurora A kinase, reveals new regulation of HURP's distribution on microtubules.Journal Reference

Kesisova IA, Nakos KC, Tsolou A, Angelis D, Lewis J, Chatzaki A, Agianian B, Giannis A, Koffa MD.

PLoS One. 2013;8(3):e58485.

Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.

 

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. TripolinA 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, TripolinA 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.

 

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