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¹ Molecular Oncology Program and ² Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and ³ Department of Chemistry, Yale University, New Haven, Connecticut

Requests for reprints: Jiandong Chen, Molecular Oncology Program, H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-903-6822; Fax: 813-903-6817. E-mail: jchen{at}moffitt.usf.edu

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 NH₂-terminal (residues 16–28) p53 -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 -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 IC₅₀ of 10 to 20 µmol/L and induce p53 accumulation and activation in cell culture at 15 to 40 µmol/L. These results suggest that p53 -helical mimetics based on the terphenyl scaffold may be developed into potent p53 activators.

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Received 12/17/04; revised 3/16/05; accepted 4/11/05.