Abstract
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.
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Acknowledgements
As this project progressed through the discovery phase, many scientists made significant contributions to its success. The authors would like to thank all past contributors to the NAE project including M. H. Foley, V. Chau, T. Gladysheva and S. Sadis. We would also like to thank D. Bowman for technical help with imaging assays, J. Blank for technical help with protein turnover assays and A. Burkhardt, P. Veiby, M. Manfredi and B. Hibner for support and guidance.
Author Contributions T.A.S., P.G.S., M.A.M., A.J.B. and J.M.G. participated in the planning, initiation, data generation and analysis of biological experiments and preparation of the manuscript. C.A.C., E.J.O., S.V., G.S.W., S.C., S.P. and S.P.L. participated in the planning, initiation, design and execution of chemical synthesis. S.A., D.P.C., A.D., H.M., M.R., J.L.G., R.E.G. and T.Talreja performed chemical synthesis; U.N. performed in vitro cell culture experiments; T.Traore and J.Z. performed in vivo anti-tumour activity and pharmacodynamic experiments; J.Y., J.J.G. and M.P.T. performed pharmacodynamic analysis experiments; A.R.L. evaluated compound potencies in cell-based assays; K.E.B. and A.M. performed immunohistochemical experiments; M.D.S. performed crystallography studies. L.R.D., J.E.B., C.F.C., M.R. and J.B.B. provided oversight of the project, reviewed and edited the manuscript.
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[Competing Interests: All authors were employees and stockholders of Millennium Pharmaceuticals Inc. during the time the studies were completed.]
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Soucy, T., Smith, P., Milhollen, M. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732–736 (2009). https://doi.org/10.1038/nature07884
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DOI: https://doi.org/10.1038/nature07884
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