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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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Systems Kinomics Demonstrates Congo Basin Monkeypox Virus Infection Selectively Modulates Host Cell Signaling Responses as Compared to West African Monkeypox Virus.
J. Kindrachuk, R. Arsenault, A. Kusalik, K. N. Kindrachuk, B. Trost, S. Napper, P. B. Jahrling, and J. E. Blaney (2012)
Mol. Cell. Proteomics 11, M111.015701
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Nanosensing protein allostery using a bivalent mouse double minute two (MDM2) assay.
A. F. Robson, T. R. Hupp, F. Lickiss, K. L. Ball, K. Faulds, and D. Graham (2012)
PNAS 109, 8073-8078
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MDM2 Protein-mediated Ubiquitination of NUMB Protein: IDENTIFICATION OF A SECOND PHYSIOLOGICAL SUBSTRATE OF MDM2 THAT EMPLOYS A DUAL-SITE DOCKING MECHANISM.
M. Sczaniecka, K. Gladstone, S. Pettersson, L. McLaren, A.-S. Huart, and M. Wallace (2012)
J. Biol. Chem. 287, 14052-14068
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A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.
Q. Zhang, S. X. Zeng, Y. Zhang, Y. Zhang, D. Ding, Q. Ye, S. O. Meroueh, and H. Lu (2012)
EMBO Mol Med. 4, 298-312
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MdmX Is Required for p53 Interaction with and Full Induction of the Mdm2 Promoter after Cellular Stress.
L. Biderman, M. V. Poyurovsky, Y. Assia, J. L. Manley, and C. Prives (2012)
Mol. Cell. Biol. 32, 1214-1225
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Small molecules that bind the Mdm2 RING stabilize and activate p53.
P. Roxburgh, A. K. Hock, M. P. Dickens, M. Mezna, P. M. Fischer, and K. H. Vousden (2012)
Carcinogenesis 33, 791-798
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p53 Pathway and Cancer Therapy.
D. P. Lane and C. F. Cheok (2012)
Am. Assoc. Cancer Res. Educ. Book 2012, 171-176
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