An Integrated Structure-based Approach for the Development of MDM2 inhibitors

Abstract

MDM2 is an oncogenic E3 ligase found to be overexpressed in a number of human cancers, leading to poor prognosis. MDM2 overexpression inhibits the function of the tumour suppressor p53, which plays a critical role in safeguarding the integrity of the genome. MDM2 ubiquitinates p53 and tags it for proteasomal degradation. MDM2 also exhibits p53-independent oncogenic activities through targeting other tumour suppressor proteins, such as Foxo3a and Rb. Thus, aberrant regulation of Mdm2 is a key factor in promotion of tumor formation and progression and represents an important cancer therapeutic target. Here, we describe an integrated structure- based approach to develop potential lead compounds for inhibition of MDM2 oncogenic activity. We established a structure-based virtual screening strategy and used the crystal structure of the MDM2:MDMX RING domain heterodimer to predict the potential “druggable” pocket on Mdm2. An in silico screening of a small molecule compound library was employed to identify the candidate compounds that could interact with the MDM2:MDMX heterodimer RING domain. Additionally, using biochemical and cellular assays, the candidate compounds were examined for their ability to inhibit MDM2 E3 ligase activity, to induce apoptosis and to inhibit cell proliferation in cancer cell lines. This study reveals that inhibition of the MDM2:MDMX RING heterodimer could be a plausible approach for the development of MDM2 inhibitors as potential anti-cancer therapeutic agents.