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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.

journal_name

Mol Cancer Ther

journal_title

Molecular cancer therapeutics

authors

Chen L,Yin H,Farooqi B,Sebti S,Hamilton AD,Chen J

doi

10.1158/1535-7163.MCT-04-0342

keywords:

subject

Has Abstract

pub_date

2005-06-01 00:00:00

pages

1019-25

issue

6

eissn

1535-7163

issn

1538-8514

pii

4/6/1019

journal_volume

4

pub_type

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