In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
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.
Vassilev
Lyubomir T
LT
Department of Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. lyubomir.vassilev@roche.com
Vu
Binh T
BT
Graves
Bradford
B
Carvajal
Daisy
D
Podlaski
Frank
F
Filipovic
Zoran
Z
Kong
Norman
N
Kammlott
Ursula
U
Lukacs
Christine
C
Klein
Christian
C
Fotouhi
Nader
N
Liu
Emily A
EA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003460:Crystallization; D018360:Crystallography, X-Ray; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008970:Molecular Weight; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013237:Stereoisomerism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007093:Imidazoles; D009687:Nuclear Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C482203:nutlin 1; C482204:nutlin 2; C482205:nutlin 3; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2