Inhibiting the p53–MDM2 interaction: an important target for cancer therapy

The tumour suppressor p53 induces cell death by apoptosis in response to various stress conditions, such as oncogene activation or DNA damage. The loss of p53 tumour-suppressor activity — either by mutation/deletion of the TP53 gene or by inhibition of the p53 protein — favours the development of cancer. The MDM2 protein is a negative regulator of p53. After binding to p53, it inhibits its transcriptional activity, favours its nuclear export and stimulates its degradation. The overexpression of MDM2 in various tumours inhibits p53, therefore favouring uncontrolled cell proliferation. The inhibition of the p53–MDM2 interaction is an attractive strategy to activate p53-mediated apoptosis in tumours with overexpressed MDM2, but wild-type p53. Several low-molecular-weight compounds and peptides that inhibit the p53–MDM2 interaction have been obtained. The peptidic inhibitors show an antiproliferative effect in tumour cells overexpressing MDM2.