Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization.
Proc Natl Acad Sci U S A
; 109(29): 11788-93, 2012 Jul 17.
Article
de En
| MEDLINE
| ID: mdl-22745160
ABSTRACT
Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines nucléaires
/
Modèles moléculaires
/
Protéine p53 suppresseur de tumeur
/
Protéines proto-oncogènes
/
Apoptose
/
Protéines proto-oncogènes c-mdm2
/
Hydantoïnes
Limites:
Humans
Langue:
En
Journal:
Proc Natl Acad Sci U S A
Année:
2012
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique