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In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Lyubomir T. Vassilev,1*Binh T. Vu,2Bradford Graves,2Daisy Carvajal,1Frank Podlaski,1Zoran Filipovic,1Norman Kong,2Ursula Kammlott,2Christine Lukacs,2Christian Klein,3Nader Fotouhi,2Emily A. Liu2
MDM2 binds the p53 tumor suppressor protein with high affinityand negatively modulates its transcriptional activity and stability.Overexpression of MDM2, found in many human tumors, effectivelyimpairs p53 function. Inhibition of MDM2-p53 interaction canstabilize p53 and may offer a novel strategy for cancer therapy.Here, we identify potent and selective small-molecule antagonistsof MDM2 and confirm their mode of action through the crystalstructures of complexes. These compounds bind MDM2 in the p53-bindingpocket and activate the p53 pathway in cancer cells, leadingto cell cycle arrest, apoptosis, and growth inhibition of humantumor xenografts in nude mice.
1 Department of Discovery Oncology, Roche Research Center, Hoffmann–La Roche, Inc., Nutley, NJ 07110, USA. 2 Department of Chemistry, Roche Research Center, Hoffmann–La Roche, Inc., Nutley, NJ 07110, USA. 3 Pharma Research, Roche Diagnostics GmbH, 82372 Penzberg, Germany.
* To whom correspondence should be addressed. E-mail: lyubomir.vassilev{at}roche.com
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C. E. Kan, J. T. Patton, G. R. Stark, and M. W. Jackson (2007)
Cancer Res.
67, 9862-9868
|Abstract »|Full Text »|PDF »
A surface on the androgen receptor that allosterically regulates coactivator binding.
E. Estebanez-Perpina, L. A. Arnold, P. Nguyen, E. D. Rodrigues, E. Mar, R. Bateman, P. Pallai, K. M. Shokat, J. D. Baxter, R. K. Guy, et al. (2007)
PNAS
104, 16074-16079
|Abstract »|Full Text »|PDF »
Inhibitors of Ubiquitin-Activating Enzyme (E1), a New Class of Potential Cancer Therapeutics.
Y. Yang, J. Kitagaki, R.-M. Dai, Y. C. Tsai, K. L. Lorick, R. L. Ludwig, S. A. Pierre, J. P. Jensen, I. V. Davydov, P. Oberoi, et al. (2007)
Cancer Res.
67, 9472-9481
|Abstract »|Full Text »|PDF »
Efficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX.
Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells.
D. J. Groskreutz, M. M. Monick, T. O. Yarovinsky, L. S. Powers, D. E. Quelle, S. M. Varga, D. C. Look, and G. W. Hunninghake (2007)
J. Immunol.
179, 2741-2747
|Abstract »|Full Text »|PDF »
Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin.
A. Efeyan, A. Ortega-Molina, S. Velasco-Miguel, D. Herranz, L. T. Vassilev, and M. Serrano (2007)
Cancer Res.
67, 7350-7357
|Abstract »|Full Text »|PDF »
Quantitative analyses reveal the importance of regulated Hdmx degradation for P53 activation.
Y. V. Wang, M. Wade, E. Wong, Y.-C. Li, L. W. Rodewald, and G. M. Wahl (2007)
PNAS
104, 12365-12370
|Abstract »|Full Text »|PDF »
Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma.
S. Singer, N. D. Socci, G. Ambrosini, E. Sambol, P. Decarolis, Y. Wu, R. O'Connor, R. Maki, A. Viale, C. Sander, et al. (2007)
Cancer Res.
67, 6626-6636
|Abstract »|Full Text »|PDF »
Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria.
