p53 α-helix mimetics antagonize p53/MDM2 interaction and activate p53

Lihong Chen, Hang Yin, Bilal Farooqi, Said Sebti, Andrew D. Hamilton, Jiandong Chen

Research output: Contribution to journalArticle

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 NH2-terminal (residues 16-28) p53 α-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 α-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 α-helical mimetics based on the terphenyl scaffold may be developed into potent p53 activators.

Original languageEnglish (US)
Pages (from-to)1019-1025
Number of pages7
JournalMolecular Cancer Therapeutics
Volume4
Issue number6
DOIs
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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