Lookup NU author(s): Dr Ian Hardcastle
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The normal functioning of the important tumor suppressor protein p53 is regulated by its binding to the MDM2 protein. Overexpression of MDM2 in some tumors is responsible for the inactivation of p53. Drugs designed to inhibit the MDM2-p53 protein-protein interaction are able to reactivate p53 activity, leading to an antitumor effect in model systems. This review details the design and discovery of small-molecule inhibitors of the MDM2-p53 interaction, which include a number of classes of potent inhibitors, such as the benzodiazepinediones, the spiro-oxindoles and the cis-imidazolines (nutlins). These prototype compounds have been used as experimental probes to determine the cellular consequences of activation of p53 in a variety of genetic backgrounds. The results to date indicate that small-molecule inhibitors of the MDM2-p53 interaction have great promise as antitumor agents, either as single agents or in combination with cytotoxic chemotherapy.
Author(s): Hardcastle IR
Publication type: Review
Publication status: Published
Journal: Drugs of the Future
ISSN (print): 0377-8282