Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy - PubMed Skip to main page content
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Review
. 2009:49:223-41.
doi: 10.1146/annurev.pharmtox.48.113006.094723.

Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy

Sanjeev Shangary  1 , Shaomeng Wang
Affiliations
Review

Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy

Sanjeev Shangary et al. Annu Rev Pharmacol Toxicol. 2009.

Abstract

Tumor suppressor p53 is an attractive cancer therapeutic target because it can be functionally activated to eradicate tumors. Direct gene alterations in p53 or interaction between p53 and MDM2 proteins are two alternative mechanisms for the inactivation of p53 function. Designing small molecules to block the MDM2-p53 interaction and reactivate the p53 function is a promising therapeutic strategy for the treatment of cancers retaining wild-type p53. This review will highlight recent advances in the design and development of small-molecule inhibitors of the MDM2-p53 interaction as new cancer therapies. A number of these small-molecule inhibitors, such as analogs of MI-219 and Nutlin-3, have progressed to advanced preclinical development or early phase clinical trials.

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Figures

Figure 1
Figure 1
Autoregulatory feedback loop of inhibition of p53 by MDM2. MDM2 directly binds to p53 and inhibits its transcriptional activity, causes ubiquitinization and proteasomal degradation of p53, and exports p53 out of the nucleus. MDMX, a homolog of MDM2, also directly binds to the transactivation domain of p53 and inhibits p53 activity, but does not cause degradation of p53. Tumor suppressor ARF binds to MDM2 and sequesters MDM2 into the nucleolus, leading to stabilization of p53.
Figure 2
Figure 2
Binding mode of a p53 peptide (PDB:1YCR) and the cis-imidazoline analog Nutlin-2 (PDB:1RV1), and the predicted binding model of spiro-oxindole analog MI-219 to MDM2. (a) Side chains of p53 residues involved in the MDM2-p53 interaction are shown in stick representation, whereas Nutlin-2 and MI-219 are shown in ball and stick representation. Nutlin-2 is shown with carbons in cyan, nitrogen in blue, oxygen in red, and bromine in brown. The predicted binding of MI-219 to MDM2 is shown with carbons in cyan, nitrogen in blue, oxygen in red, fluorine in light blue, and chlorine in green. The surface representation of MDM2 in each case is shown with carbons in gray, nitrogen in blue, oxygen in red, and sulfur in yellow. Hydrogen bonds are depicted with yellow lines and hydrogen atoms are excluded for clarity. The PyMOL program was used to generate figures. (b) Chemical structures of Nutlin-3a and MI-219, the two potent and specific small-molecule inhibitors of the MDM2-p53 interaction.
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