Discovery and Development of Aurora Kinase Inhibitors as Anticancer Agents

Pollard, John R.; Mortimore, Michael

doi:10.1021/jm8012129

Cited by 171 publications

(173 citation statements)

References 142 publications

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“…To do this, we utilized a pan-Aurora inhibitor, Danusertib, which has shown preclinical and clinical efficacy (5,6). Nocodazole-or taxol-arrested mitotic HeLa cells were treated with Danusertib (1 M) for 4 h, and MYBBP1A phosphorylation status was then investigated.…”

Section: A Kinase Substrate Search Identifies a 160-kda Protein As Amentioning

confidence: 99%

“…Thus, Aurora kinases represent attractive targets for anti-cancer drug development. Indeed, small molecule inhibitors have been developed and are currently being tested in clinical trials (5,6). The identification of mechanism of action-related biomarkers and the discovery of new substrates is of crucial importance not only to better characterize the cellular role of the Aurora kinases but also to provide a clear readout of the in vivo activity of compounds.…”

mentioning

confidence: 99%

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Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Perrera

Colombo

Valsasina

et al. 2010

Journal of Biological Chemistry

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Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.

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Section: A Kinase Substrate Search Identifies a 160-kda Protein As Amentioning

confidence: 99%

mentioning

confidence: 99%

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Perrera

Colombo

Valsasina

et al. 2010

Journal of Biological Chemistry

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“…Aurora-A is an oncogene-associated serine/threonine kinase active at the G 2 /M transition of mitosis and is currently the target of a number of drug discovery programs (7,8). It localizes to the centrosome and to the mitotic spindle and binds to a number of different protein partners in vivo, the best characterized of which is TPX2.…”

mentioning

confidence: 99%

Activation of Aurora-A Kinase by Protein Partner Binding and Phosphorylation Are Independent and Synergistic

Dodson¹,

Bayliss

2012

Journal of Biological Chemistry

126

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Background: Phosphorylation and TPX2 act together to stabilize the active conformation of Aurora-A. Results: TPX2 activates unphosphorylated Aurora-A, although phosphorylation makes a 2-fold greater energetic contribution to catalysis than TPX2. Conclusion: Either activator partially stabilizes the active conformation and stimulates kinase activity. Significance: Our revised model of kinase activation and mechanistic analysis might be applicable to other kinases.

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“…Hesperadin, ZM447439, MK0457 previously VX-680, PHA-680632, AZD1152, MLN8054, CYC116, in ref. [19]). These AK inhibitors can be subdivided into three general classes: those that have selectivity for AK-A over AK-B, those with selectivity for AK-B over AK-A, and those that are potent inhibitors of both AK-A and AK-B.…”

Section: Aurora Kinases and Cancermentioning

confidence: 99%

“…In this paper, we considered the compound CYC116 ( [19,20]). It has previously been shown that CYC116 inhibits both AK-A and AK-B and it is thought that its main cite of action is the spindle assembly checkpoint.…”

Section: Modelling the Dynamic Effects Of Drug Dose On Multi-cellularmentioning

confidence: 99%

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

Kamei

Jackson

Zheleva

et al. 2010

J Pharmacokinet Pharmacodyn

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The spindle assembly checkpoint is a cell cycle surveillance mechanism that ensures the proper separation of chromosomes prior to cell division at mitosis. Aurora kinases play critical roles in mitotic progression and hence small-molecule inhibitors of Aurora kinases have been developed as a new class of potential anticancer drugs. In this paper we present for the first time an integrated pharmacokinetic-pharmacodynamic model of the functional effects of CYC116 (a known inhibitor of Aurora kinases A and B) on the spindle assembly checkpoint. We use the model to simulate two common experimental systems: cell culture and p.o. dosing of mice and present predictions of the effects of CYC116 for a range of doses and drug scheduling regimes. The model reveals that a critical peak drug concentration is required to cause aberrant kinetochore-microtubule attachments. The model also predicts that provided this threshold concentration is exceeded, a high total oral dose causes a high number of aberrant attachments within any given damaged cell. However, the proportion of cells which enter anaphase with aberrant attachments is associated with the total length of time for which the plasma concentration is maintained above the threshold. Moreover, our model reveals that the length of prometaphase/metaphase is a nonlinear function of drug dose and this time period can be extended or shortened. Finally, a strong saturation effect on CYC116 efficacy is predicted by the model. We discuss how these predictions may have implications for further drug trials using CYC116 and other similar AK inhibitors.

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Discovery and Development of Aurora Kinase Inhibitors as Anticancer Agents

Cited by 171 publications

References 142 publications

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Activation of Aurora-A Kinase by Protein Partner Binding and Phosphorylation Are Independent and Synergistic

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

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