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  • Title: Inhibitors of MDM2 and MDMX: a structural perspective.
    Author: Riedinger C, McDonnell JM.
    Journal: Future Med Chem; 2009 Sep; 1(6):1075-94. PubMed ID: 21425995.
    Abstract:
    p53 is a potent tumor suppressor with a crucial role in preventing uncontrolled cell proliferation and is therefore frequently deleted or mutated in cancer. For tumors with wild-type p53, its function can be overcome by overactive cellular antagonists, such as the ubiquitin ligase murine double minute clone 2 (MDM2). Restoring p53 activity by inhibiting MDM2 in such cancers can eradicate tumors. Consequently, the MDM2-p53 interaction has been extensively targeted for inhibition by small molecules. In recent years, MDM2-like protein (MDMX), another key downregulator of p53, has gained increasing importance as an additional target for drug development, in order to provide a complementary approach to MDM2 inhibition. In this review, we describe how detailed structural knowledge of the MDM2-p53 interface and, more recently, of the MDMX-p53 interaction have helped advance the development of inhibitors against the two targets. We present a summary of the functional biochemistry of MDM2, MDMX and p53 as well as their interactions and examine recent progress in the development of inhibitors of MDM2 and MDMX.
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