title: p53 alpha-Helix mimetics antagonize p53/MDM2 interaction and activate p53.
abstract: 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.
authors.affiliation: Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
authors.forename: Bilal
authors.initials: B
authors.lastname: Farooqi
authors.forename: Said
authors.initials: S
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
mesh_terms: 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*
chemical_list: 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