QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 15 August 2006
doi: 10.1242/jcs.03145

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: jcs.03145v1 119/17/3664    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Girdler, F. Articles by Taylor, S. S. Search for Related Content PubMed PubMed Citation Articles by Girdler, F. Articles by Taylor, S. S.

Validating Aurora B as an anti-cancer drug target

¹ Faculty of Life Sciences, Michael Smith Building, Oxford Road, University of Manchester, Manchester, M13 9PT, UK
² Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Cheshire, SK10 4TG, UK

^* Author for correspondence (e-mail: stephen.taylor{at}manchester.ac.uk)

Accepted 20 June 2006

The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anti-cancer therapeutics. Several Aurora kinase inhibitors have been described including ZM447439, which prevents chromosome alignment, spindle checkpoint function and cytokinesis. Subsequently, ZM447439-treated cells exit mitosis without dividing and lose viability. Because ZM447439 inhibits both Aurora A and B, we set out to determine which phenotypes are due to inhibition of which kinase. Using molecular genetic approaches, we show that inhibition of Aurora B kinase activity phenocopies ZM447439. Furthermore, a novel ZM compound, which is 100 times more selective for Aurora B over Aurora A in vitro, induces identical phenotypes. Importantly, inhibition of Aurora B kinase activity induces a penetrant anti-proliferative phenotype, indicating that Aurora B is an attractive anti-cancer drug target. Using molecular genetic and chemical-genetic approaches, we also probe the role of Aurora A kinase activity. We show that simultaneous repression of Aurora A plus induction of a catalytic mutant induces a monopolar phenotype. Consistently, another novel ZM-related inhibitor, which is 20 times as potent against Aurora A compared with ZM447439, induces a monopolar phenotype. Expression of a drug-resistant Aurora A mutant reverts this phenotype, demonstrating that Aurora A kinase activity is required for spindle bipolarity in human cells. Because small molecule-mediated inhibition of Aurora A and Aurora B yields distinct phenotypes, our observations indicate that the Auroras may present two avenues for anti-cancer drug discovery.

Key words: ZM447439, Hesperadin, VX-680, Drug-resistance, Chemical genetics

Related articles in JCS:

Cancer targets - Aurora B or alias

JCS 2006 119: 1701. [Full Text]  

This article has been cited by other articles:

				J. E. Swain, J. Ding, J. Wu, and G. D. Smith Regulation of spindle and chromatin dynamics during early and late stages of oocyte maturation by aurora kinases Mol. Hum. Reprod., May 1, 2008; 14(5): 291 - 299. [Abstract] [Full Text] [PDF]

				A. M. D'Alise, G. Amabile, M. Iovino, F. P. Di Giorgio, M. Bartiromo, F. Sessa, F. Villa, A. Musacchio, and R. Cortese Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1140 - 1149. [Abstract] [Full Text] [PDF]

				E. Walsby, V. Walsh, C. Pepper, A. Burnett, and K. Mills Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts Haematologica, May 1, 2008; 93(5): 662 - 669. [Abstract] [Full Text] [PDF]

				O. Gautschi, J. Heighway, P. C. Mack, P. R. Purnell, P. N. Lara Jr., and D. R. Gandara Aurora Kinases as Anticancer Drug Targets Clin. Cancer Res., March 15, 2008; 14(6): 1639 - 1648. [Abstract] [Full Text] [PDF]

				A. R. Barr and F. Gergely Aurora-A: the maker and breaker of spindle poles J. Cell Sci., September 1, 2007; 120(17): 2987 - 2996. [Abstract] [Full Text] [PDF]

				K. Hoar, A. Chakravarty, C. Rabino, D. Wysong, D. Bowman, N. Roy, and J. A. Ecsedy MLN8054, a Small-Molecule Inhibitor of Aurora A, Causes Spindle Pole and Chromosome Congression Defects Leading to Aneuploidy Mol. Cell. Biol., June 15, 2007; 27(12): 4513 - 4525. [Abstract] [Full Text] [PDF]

				P. J. LeRoy, J. J. Hunter, K. M. Hoar, K. E. Burke, V. Shinde, J. Ruan, D. Bowman, K. Galvin, and J. A. Ecsedy Localization of Human TACC3 to Mitotic Spindles Is Mediated by Phosphorylation on Ser558 by Aurora A: A Novel Pharmacodynamic Method for Measuring Aurora A Activity Cancer Res., June 1, 2007; 67(11): 5362 - 5370. [Abstract] [Full Text] [PDF]

				B. T. Keady, P. Kuo, S. E. Martinez, L. Yuan, and L. E. Hake MAPK interacts with XGef and is required for CPEB activation during meiosis in Xenopus oocytes J. Cell Sci., March 15, 2007; 120(6): 1093 - 1103. [Abstract] [Full Text] [PDF]

				M. G. Manfredi, J. A. Ecsedy, K. A. Meetze, S. K. Balani, O. Burenkova, W. Chen, K. M. Galvin, K. M. Hoar, J. J. Huck, P. J. LeRoy, et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase PNAS, March 6, 2007; 104(10): 4106 - 4111. [Abstract] [Full Text] [PDF]