Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics.
p53 regulates a key pathway which protects normal tissues from tumor development that may result from diverse forms of stress. In the absence of stress, growth suppressive and proapoptotic activity of p53 is inhibited by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 antagonists could activate p53 and may offer a novel therapeutic approach to cancer. Recently, we identified the first potent and selective low molecular weight inhibitors of MDM2-p53 binding, the Nutlins. These molecules activate the p53 pathway and suppress tumor growth in vitro and in vivo. They represent valuable new tools for studying the p53 pathway and its defects in cancer. Nutlins induce p53-dependent apoptosis in human cancer cells but appear cytostatic to proliferating normal cells. Their potent activity against osteosarcoma xenografts suggests that MDM2 antagonists may have clinical utility in the treatment of tumors with wild-type p53.
Roche Research Center, Hoffman-La Roche Inc., Nutley, New Jersey 07110, USA. hyubomir.vassilev@roche.com
Lyubomir T
LT
Vassilev
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D003470:Culture Media; D007093:Imidazoles; D009687:Nuclear Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C482203:nutlin 1; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2