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Science 303 (5659): 844-848

Copyright © 2004 by the American Association for the Advancement of Science

In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2

Lyubomir T. Vassilev,1* Binh T. Vu,2 Bradford Graves,2 Daisy Carvajal,1 Frank Podlaski,1 Zoran Filipovic,1 Norman Kong,2 Ursula Kammlott,2 Christine Lukacs,2 Christian Klein,3 Nader Fotouhi,2 Emily A. Liu2

Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor 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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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Z. Wen, D. Pyeon, Y. Wang, P. Lambert, W. Xu, and P. Ahlquist (2012)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
The Human Transcriptome During Nontyphoid Salmonella and HIV Coinfection Reveals Attenuated NF{kappa}B-Mediated Inflammation and Persistent Cell Cycle Disruption.
F. Schreiber, D. J. Lynn, A. Houston, J. Peters, G. Mwafulirwa, B. B. Finlay, F. S. L. Brinkman, R. E. W. Hancock, R. S. Heyderman, G. Dougan, et al. (2011)
The Journal of Infectious Disease 204, 1237-1245
   Abstract »    Full Text »    PDF »
Tumor suppressor protein (p)53, is a regulator of NF-{kappa}B repression by the glucocorticoid receptor.
S. H. Murphy, K. Suzuki, M. Downes, G. L. Welch, P. De Jesus, L. J. Miraglia, A. P. Orth, S. K. Chanda, R. M. Evans, and I. M. Verma (2011)
PNAS 108, 17117-17122
   Abstract »    Full Text »    PDF »
Human Oncoprotein MDM2 Up-regulates Expression of NF-{kappa}B2 Precursor p100 Conferring a Survival Advantage to Lung Cells.
C. Vaughan, L. Mohanraj, S. Singh, C. I. Dumur, M. Ramamoorthy, C. T. Garrett, B. Windle, W. A. Yeudall, S. Deb, and S. P. Deb (2011)
Genes & Cancer 2, 943-955
   Abstract »    Full Text »    PDF »
Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect.
C. Zhang, M. Lin, R. Wu, X. Wang, B. Yang, A. J. Levine, W. Hu, and Z. Feng (2011)
PNAS 108, 16259-16264
   Abstract »    Full Text »    PDF »
Physical and Functional Antagonism between Tumor Suppressor Protein p53 and Fortilin, an Anti-apoptotic Protein.
Y. Chen, T. Fujita, D. Zhang, H. Doan, D. Pinkaew, Z. Liu, J. Wu, Y. Koide, A. Chiu, C. C.-J. Lin, et al. (2011)
J. Biol. Chem. 286, 32575-32585
   Abstract »    Full Text »    PDF »
Human NK Cells Are Alerted to Induction of p53 in Cancer Cells by Upregulation of the NKG2D Ligands ULBP1 and ULBP2.
S. Textor, N. Fiegler, A. Arnold, A. Porgador, T. G. Hofmann, and A. Cerwenka (2011)
Cancer Res. 71, 5998-6009
   Abstract »    Full Text »    PDF »
Transient protein-protein interactions.
S. E. Acuner Ozbabacan, H. B. Engin, A. Gursoy, and O. Keskin (2011)
Protein Eng. Des. Sel. 24, 635-648
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Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay.
A. G. Herman, M. Hayano, M. V. Poyurovsky, K. Shimada, R. Skouta, C. Prives, and B. R. Stockwell (2011)
Cancer Discovery 1, 312-325
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Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation.
T. Hashimoto, T. Ichiki, J. Ikeda, E. Narabayashi, H. Matsuura, R. Miyazaki, K. Inanaga, K. Takeda, and K. Sunagawa (2011)
Cardiovasc Res 91, 711-719
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Structural conservation of druggable hot spots in protein-protein interfaces.
D. Kozakov, D. R. Hall, G.-Y. Chuang, R. Cencic, R. Brenke, L. E. Grove, D. Beglov, J. Pelletier, A. Whitty, and S. Vajda (2011)
PNAS 108, 13528-13533
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Validation of MdmX as a therapeutic target for reactivating p53 in tumors.
D. Garcia, M. R. Warr, C. P. Martins, L. Brown Swigart, E. Passegue, and G. I. Evan (2011)
Genes & Dev. 25, 1746-1757
   Abstract »    Full Text »    PDF »
p53 binding to nucleosomes within the p21 promoter in vivo leads to nucleosome loss and transcriptional activation.
O. Laptenko, R. Beckerman, E. Freulich, and C. Prives (2011)
PNAS 108, 10385-10390
   Abstract »    Full Text »    PDF »

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