An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
| Autor: | Teresa A. Soucy, Peter G. Smith, Michael A. Milhollen, Allison J. Berger, James M. Gavin, Sharmila Adhikari, James E. Brownell, Kristine E. Burke, David P. Cardin, Stephen Critchley, Courtney A. Cullis, Amanda Doucette, James J. Garnsey, Jeffrey L. Gaulin, Rachel E. Gershman, Anna R. Lublinsky, Alice McDonald, Hirotake Mizutani, Usha Narayanan, Edward J. Olhava, Stephane Peluso, Mansoureh Rezaei, Michael D. Sintchak, Tina Talreja, Michael P. Thomas, Tary Traore, Stepan Vyskocil, Gabriel S. Weatherhead, Jie Yu, Julie Zhang, Lawrence R. Dick, Christopher F. Claiborne, Mark Rolfe, Joseph B. Bolen, Steven P. Langston |
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| Rok vydání: | 2009 |
| Předmět: |
NEDD8 Protein
Ubiquitin-activating enzyme Transplantation Heterologous Antineoplastic Agents Cyclopentanes Ubiquitin-Activating Enzymes NEDD8 Mice Ubiquitin Cell Line Tumor Neoplasms Animals Humans Enzyme Inhibitors Ubiquitins Cells Cultured Multidisciplinary biology Cullin Proteins Cell biology Pyrimidines Pevonedistat Proteasome Cancer cell biology.protein Female Neddylation Proteasome Inhibitors Cullin |
| Zdroj: | Nature. 458:732-736 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer. |
| Databáze: | OpenAIRE |
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