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| Item Type: | Article |
|---|---|
| Title: | Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma |
| Creators Name: | Brockmann, M., Poon, E., Berry, T., Carstensen, A., Deubzer, H.E., Rycak, L., Jamin, Y., Thway, K., Robinson, S.P., Roels, F., Witt, O., Fischer, M., Chesler, L. and Eilers, M. |
| Abstract: | Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy. |
| Keywords: | Antineoplastic Agents, Aurora Kinase A, Aurora Kinases, Azepines, Benzazepines, Cell Cycle Proteins, Cyclohexanecarboxylic Acids, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Neuroblastoma, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-myc, Pyrimidines, Thiazoles, Tumor Cell Line, Ubiquitin-Protein Ligases, Animals, Mice |
| Source: | Cancer Cell |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 24 |
| Number: | 1 |
| Page Range: | 75-89 |
| Date: | 8 July 2013 |
| Additional Information: | Erratum in: Cancer Cell 30(2):357. |
| Official Publication: | https://doi.org/10.1016/j.ccr.2013.05.005 |
| PubMed: | View item in PubMed |
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