Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

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.

The role of miRNAs in MDMX‐p53 interplay

“…MDMX, as a critical negative regulator of p53 tumor suppressor, has gradually evolved into a promising cancer therapeutic target with a high similar function and structure to MDM2. 16 The abnormal expression of miRNAs and MDMX are very common in different types of human cancer. Previous studies have suggested that the expression level of MDMX is correlated to the overall survival of patients with salivary gland cancer (SGC), chronic lymphocytic leukemia (CLL), and soft tissue sarcomas.…”

“…44 Considering that blocking MDMX-p53 interaction or inhibiting MDMX expression is effective for restoring the tumor suppressor activity of p53, MDMX could be considered as one of the most promising molecular targets for developing anticancer therapeutics. 16,[45][46][47][48][49] Of course, miRNAs that regulate the MDMX-p53 pathway can also play a pivotal role in human cancer.…”

“…have been developed and shown anticancer activity in vitro and in vivo. 16,47,[80][81][82][83][84][85][86] However, none of these inhibitors has been approved for clinical treatment. 7,87 Almost all of these inhibitors have been designed to reactivate wild-type p53 by inhibiting MDM2 and/or MDMX, and it is speculated that these inhibitors may have little or no inhibitory effect on human cancer cells with p53 mutation or p53 deletion.…”

“…MDMX has been widely considered as a therapeutic target for cancer therapy. 16 Several miRNAs have been found to restore the tumor suppressor function of p53 by negatively regulating the expression of MDMX. Here, we make a summary of miRNAs that regulate p53 level via targeting MDMX as well as their roles in cancer.…”

“…[12][13][14][15] MDMX has been implicated in the initiation and progression of human cancers and © 2021 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd is becoming an emerging molecular target for developing anticancer therapeutics. 16,17 MicroRNAs (miRNAs), produced by DNA transcription, are kinds of small single-stranded noncoding RNA with a length of 19-24 nucleotides. [18][19][20] MiRNAs partially or completely complement the 3′-untranslated region (3′-UTR) of the target mRNAs, thus controlling the expression of target genes by cutting the transcripts or inhibiting the translation of the transcripts.…”