Publication Date:
2004-01-06
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vassilev, Lyubomir T -- Vu, Binh T -- Graves, Bradford -- Carvajal, Daisy -- Podlaski, Frank -- Filipovic, Zoran -- Kong, Norman -- Kammlott, Ursula -- Lukacs, Christine -- Klein, Christian -- Fotouhi, Nader -- Liu, Emily A -- New York, N.Y. -- Science. 2004 Feb 6;303(5659):844-8. Epub 2004 Jan 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. lyubomir.vassilev@roche.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14704432" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis/*drug effects
;
Binding Sites
;
Cell Cycle/drug effects
;
Cell Division/*drug effects
;
Cell Line
;
Cell Line, Tumor
;
Cell Survival/drug effects
;
Crystallization
;
Crystallography, X-Ray
;
Cyclin-Dependent Kinase Inhibitor p21
;
Cyclins/metabolism
;
Dose-Response Relationship, Drug
;
Gene Expression
;
Genes, p53
;
Humans
;
Hydrophobic and Hydrophilic Interactions
;
Imidazoles/chemistry/metabolism/*pharmacology
;
Mice
;
Mice, Nude
;
Models, Molecular
;
Molecular Weight
;
NIH 3T3 Cells
;
Neoplasm Transplantation
;
Neoplasms, Experimental/drug therapy/metabolism/*pathology
;
*Nuclear Proteins
;
Phosphorylation
;
Piperazines/chemistry/metabolism/*pharmacology
;
Protein Conformation
;
Proto-Oncogene Proteins/*antagonists & inhibitors/chemistry/metabolism
;
Proto-Oncogene Proteins c-mdm2
;
Stereoisomerism
;
Transplantation, Heterologous
;
Tumor Suppressor Protein p53/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
