In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
2004; American Association for the Advancement of Science; Volume: 303; Issue: 5659 Linguagem: Inglês
10.1126/science.1092472
ISSN1095-9203
AutoresLyubomir T. Vassilev, Binh Thanh Vu, Bradford Graves, Daisy Carvajal, Frank Podlaski, Zoran Filipovic, Norman Kong, U. Kammlott, Christine Lukacs, Christian Klein, Nader Fotouhi, Emily A. Liu,
Tópico(s)Ubiquitin and proteasome pathways
ResumoMDM2 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.
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