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Originally published in Science Express on 2 January 2004
Science 6 February 2004:
Vol. 303. no. 5659, pp. 844 - 848
DOI: 10.1126/science.1092472
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Reports

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

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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