Small-Molecule Inhibitors of p53-MDM2 Interaction: the 2006-2010 Update

Melissa      Millard; Divya      Pathania; Fedora      Grande; Shili      Xu; Nouri      Neamati

Abstract

Increasing knowledge of the relationship between p53 and MDM2 has led to development of potential small molecule inhibitors useful for clinical studies. Herein, we discuss the patented (2006-2010) inhibitors of p53-MDM2 interaction. The anticancer agents discussed in this review belong to several different chemical classes including benzodiazepinediones, cis-imidazolines, oxindoles, spirooxindoles, and numerous miscellaneous groups. This review also provides comprehensive information on inhibitors of p53-MDM2 interaction that are currently being tested in clinical trials. It is important to note that many of the disclosed inhibitors need further validation to be considered as bona fide inhibitors of p53-MDM2 interaction and some will not be further considered for future studies. On the other hand, JNJ-26854165, a novel tryptamine derivative and RG7112, a cis-imidazoline representative have shown promising results in early phases of trials in cancer patients. AT-219, a spiroindolinone in late stage preclinical studies is a likely candidate to proceed into clinical trials. It remains to be seen how these inhibitors will perform in future clinical studies as single agents and in combination with the currently approved chemotherapeutic agents.

Keywords: p53, MDM2, protein-protein interaction, nutlin, benzodiazepinediones, cis-imidazolines, oxindoles, spiro-oxindoles, small molecule anticancer agents, MDM2 antagonists, p53 wild type, spiroindolinone, JNJ- 26854165, RG7112, AT-219