Abstract
The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.
Highlights
In 1996, Shvarts et al discovered a new binding protein of the tumor suppressor p53, which is highly homologous to a critical negative regulator of p53, i.e., the oncoprotein MDM2 [1]
Due to the findings that MDMX is essential for controlling p53 activity during embryonic development in vivo [10,11,12], as well as that MDMX directly interacts with MDM2 and plays an important role in enhancing MDM2’s activity and stabilizing MDM2 protein [13, 14], MDMX started to be recognized as a key player in the p53-MDM2/MDMX circuitry [15,16,17,18]
Over the last two-and-a-half decades, MDMX has been developed from the status of the little brother of its well-studied and important “older” relative MDM2 to another key negative regulator of p53 in embryonic and, perhaps most importantly, cancer cells
Summary
In 1996, Shvarts et al discovered a new binding protein of the tumor suppressor p53, which is highly homologous to a critical negative regulator of p53, i.e., the oncoprotein MDM2 (murine double minute 2) [1]. Several MDMX-targeting strategies (Figure 3) have been proposed to develop MDMX inhibitors, including [1] directly blocking p53-MDMX interaction, [2] inhibiting MDMX expression, and [3] inducing MDMX protein degradation. SAH-p53-8 has further been shown to block the p53-MDMX binding and activate the p53 signaling pathway, inhibiting cancer cell viability, inducing apoptosis, and overcoming MDMX-mediated cancer chemoresistance in vitro and in vivo.
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