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 language | English (US) |
---|---|
Pages (from-to) | 1019-1025 |
Number of pages | 7 |
Journal | Molecular Cancer Therapeutics |
Volume | 4 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2005 |
ASJC Scopus subject areas
- Oncology
- Cancer Research