Aurora A and B kinases as targets for cancer: will they be selective for tumors?

Matthews, Nick; Visintin, Cristina; Hartzoulakis, Basil; Jarvis, Ashley; Selwood, David L.

doi:10.1586/14737140.6.1.109

Cited by 73 publications

(69 citation statements)

References 66 publications

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“…Largely because Aurora A is overexpressed in many cancers, a number of Aurora inhibitors have been developed, several of which are being tested in the clinic for anticancer activity 6,7 . The best characterized Aurora inhibitors described thus far include ZM447439, hesperadin, VX-680 and MLN-8054, and all are useful tools for probing the roles of cellular Aurora kinase activity.…”

Section: The Aurora B Kinasesmentioning

confidence: 99%

Recognizing and exploiting differences between RNAi and small-molecule inhibitors

2007

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The biology of RNA interference has greatly facilitated analysis of loss-of-function phenotypes, but correlating these phenotypes with small-molecule inhibition profiles is not always straightforward. We examine the rationale of comparing RNA interference to pharmacological intervention in chemical biology.RNA-mediated silencing has rapidly arisen as a critical tool in the arsenal of the molecular biologist. This strategy facilitates the generation of loss-of-function mutations in individual cells or in whole organisms and enables investigators to interrogate the impact of these mutations. The rapid proliferation of small interfering RNA (siRNA) experimentation has provided a complementary view to traditional pharmacological approaches (which allow perturbation of a target through small-molecule inhibition) and to genetic knockouts (which generate loss-of-function events more often in whole organisms than in individual cells) (Fig. 1). These three modalities are typically seen as capable of providing answers to the same question: what is the phenotype when protein X is inactivated? Because genetic knockouts are often difficult to apply to cell culture and typically require a significant investment of resources and time (and are often compounded by compensatory changes in development and by lethality-both of which complicate interpretation), we limit this Commentary to the study of RNA interference (RNAi) and pharmacological manipulation in cells.In many cases the answers arrived at by RNAi and pharmacology are aligned. The purpose of this Commentary is (i) to highlight situations in which RNAi and small-molecule approaches diverge in reading out complementary biology, (ii) to provide specific examples where the absence of a protein shows a different phenotype than inhibition of a protein that is physically intact and (iii) to highlight the importance of recognizing these differences. The motivation behind seeking an answer to the question "Is RNAi of target X likely to induce the same phenotype as a small-molecule inhibitor of target X?" is two-fold. First, in a target discovery mode, RNAi has proven powerful for identifying unexpected pathway components in many normal and disease processes. How likely is it that one could produce a small molecule to match the RNAi-induced phenotype? The second question is in some sense the reverse: on discovery of a new small-molecule entity, its true specificity for the stated target is often debatable. Thus it is often commented that the investigator should

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Section: The Aurora B Kinasesmentioning

confidence: 99%

Recognizing and exploiting differences between RNAi and small-molecule inhibitors

2007

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“…The Aurora kinases, a family of mitotic regulators, have received much attention as potential targets for novel anticancer therapeutics (Andrews, 2005; Keen and Taylor, 2004;Matthews et al, 2006). This enthusiasm comes largely from early observations showing that Aurora A is overexpressed in human cancers and has oncogenic properties in vitro (Bischoff et al, 1998;Zhou et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Validating Aurora B as an anti-cancer drug target

Girdler

Gascoigne

Eyers

et al. 2006

Journal of Cell Science

267

272

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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.

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“…In earlier publications, a number of quinazoline-based series have been described as Aurora kinase inhibitors [2,22,[42][43][44] . Particularly, the p-benzamidoanilinoquinazoline series was shown to inhibit Aurora A and Aurora B equipotently.…”

Section: Discussionmentioning

confidence: 99%

Structural studies of B-type Aurora kinase inhibitors using computational methods

et al. 2010

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Aurora A and B kinases as targets for cancer: will they be selective for tumors?

Cited by 73 publications

References 66 publications

Recognizing and exploiting differences between RNAi and small-molecule inhibitors

Recognizing and exploiting differences between RNAi and small-molecule inhibitors

Validating Aurora B as an anti-cancer drug target

Structural studies of B-type Aurora kinase inhibitors using computational methods

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