p53 alpha-Helix mimetics antagonize p53/MDM2 interaction and activate p53.
Overexpression or hyperactivation of MDM2 contributes to functional inactivation of wild-type p53 in nearly 50% of tumors. Inhibition of p53 by MDM2 depends on binding between an NH(2)-terminal (residues 16-28) p53 alpha-helical peptide and a hydrophobic pocket on MDM2, presenting an attractive target for development of inhibitors against tumors expressing wild-type p53. Here we report that novel p53 alpha-helical peptide mimics based on a terphenyl scaffold can inhibit MDM2-p53 binding in vitro and activate p53 in vivo. Several active compounds have been identified that inhibit MDM2-p53 binding in an ELISA assay with IC(50) of 10 to 20 micromol/L and induce p53 accumulation and activation in cell culture at 15 to 40 micromol/L. These results suggest that p53 alpha-helical mimetics based on the terphenyl scaffold may be developed into potent p53 activators.
Chen
Lihong
L
Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Yin
Hang
H
Farooqi
Bilal
B
Sebti
Said
S
Hamilton
Andrew D
AD
Chen
Jiandong
J
D000595:Amino Acid Sequence; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013730:Terphenyl Compounds; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2