An Update on MDMX and Dual MDM2/X Inhibitors

Abstract

The tumor suppressor protein p53 is inactivated in all types of human cancers, either by negative regulation, by mutation or deletion of its gene. Specifically, in tumors that retain wild-type (wt) p53 status, p53 is inactivated by interaction with negative regulators, such as MDM2 and MDMX. These two proteins are found to be overexpressed in several different types of cancers, and the restoration of p53 activity by inhibition of these proteins is now considered an important approach for cancer treatment. The first studies using this strategy to reactivate wt p53 were focused on the development of small molecules that could inhibit MDM2. In this way, p53 could be liberated and act again as a tumor suppressor. From these studies, nine small molecules have reached clinical trials. More recently, MDMX was also identified as an important therapeutic target to efficiently reactivate wt p53, and it is now considered that, for full p53 reactivation, dual inhibition of MDM2 and MDMX is required. In this review we will focus on the most recent advances in the discovery of novel small molecules and stapled peptides that act as selective MDMX inhibitors or as dual MDM2/X inhibitors.

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

“…143 Discovery efforts for potent MDMX inhibitors in the last 10 years have shown some promising results. 144 Studies support that for full TP53 activation, dual inhibition of MDM2 and MDMX might be required. 143 This prompted the development of a stapled alpha-helical cell-penetrating peptide, ALRN-…”

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Over the past few decades, much research has been dedicated to unraveling the roles of MDM2 in cancer initiation, progression, metastasis, and drug resistance . Inhibiting MDM2 has been demonstrated to be a promising strategy for treating and preventing human cancers . In recent years, increasing attention has been focused on the noncarcinogenic roles of MDM2 in noncancer diseases.…”

“…The MDM2‐p53 signaling axis is one of the most‐investigated pathways in human cancers and has become a classic model system for the design and development of protein‐protein interaction inhibitors . Following the characterization of the crystal structures of MDM2‐p53 complexes, several classes of MDM2 inhibitors with desirable pharmaceutical properties have been developed and characterized for treating and preventing cancer in preclinical models and a few have entered clinical trials . Of note, almost all of the SMIs of MDM2 in clinical trials (Figure ) target the binding of MDM2 and p53 and exert their anticancer effects primarily by activating the p53 pathway in cells with WT p53 .…”

“…Following the characterization of the crystal structures of MDM2‐p53 complexes, several classes of MDM2 inhibitors with desirable pharmaceutical properties have been developed and characterized for treating and preventing cancer in preclinical models and a few have entered clinical trials . Of note, almost all of the SMIs of MDM2 in clinical trials (Figure ) target the binding of MDM2 and p53 and exert their anticancer effects primarily by activating the p53 pathway in cells with WT p53 . From these, nine MDM2 inhibitors have entered clinical trials and seven are still in clinical evaluation .…”

“…In addition, MDM2 has been evaluated as a biomarker for the diagnosis and prognostication of various diseases, and for predicting the response of the disease to conventional therapies . Several recent reviews have comprehensively discussed the roles of MDM2 in tumorigenesis, its amplification and expression in various human cancers, its inhibitory effects on p53, its uses as a cancer biomarker, and the cancer therapeutic agents that specifically target MDM2 protein …”