This study reveals that Mdmx can control cell invasion through RhoA stabilisation/activation, which is potentially linked to the reported anti-oncogenic functions of Mdmx. As inhibitors of the NEDD8 pathway are in clinical trials, the status of Mdmx may be a critical determinant for the anti-tumour effects of these inhibitors.

This review introduces the structure, distribution, and regulation of the MDMX, summarizes the structural features and structure-activity relationships (SARs) of MDMX ligands, and focuses on the differences between MDMX and MDM2 in these aspects. Our purpose of this work is to propose potential strategies to achieve the specific targeting of MDMX.

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1

In conclusion, miR-34c-5p was down-regulated in BAS and may inhibit fibroblast proliferation differentiation and EMT in BAS via the MDMX/p53 signaling axis. These findings expand the understanding of the role of miR-34c-5p and will help develop new treatment strategies for BAS.

P1, N=84, Not yet recruiting, Roswell Park Cancer Institute

CCDC106 overexpression downregulates the cellular level of p53 and Mdm2/MdmX, and decreased p53 reversibly downregulates the cellular level of CCDC106. Our work provides a molecular mechanism by which CCDC106 regulates the cellular levels of p53 and Mdm2/MdmX.

P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2023 --> Apr 2025 | Trial primary completion date: Jul 2023 --> Apr 2025

We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

P1, N=21, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | N=69 --> 21

A recent report describes that ALRN-6924, an ATSP-7041 analog, inhibited OATP activities in vivo; therefore, we focused on the interaction between ATSP-7041 and OATP1B1 to demonstrate that ATSP-7041, as a higher molecular weight stapled peptide, is a substrate and strong inhibitor of OATP1B1 activity. Our findings demonstrated the possibility of transporter-mediated DDI potential by high molecular weight stapled peptides and the necessity of their evaluation for drug development.

P1, N=69, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2023 --> Sep 2023 | Trial primary completion date: Jun 2023 --> Sep 2023

In summary, we demonstrated that high MDMX expression, in a p53-independent manner, was associated with higher HMA resistance and significantly worse survival in MDS patients. Moreover, drug treatment tests suggested the potential of combinatorial therapy of MDMX inhibitor along with HMA. Further experiments and prospectivestudies are warranted to support these observations.

P1, N=69, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

Two new drugs, Trilaciclib and ALRN-6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration.

Summary: Recent advances in our understanding of the molecular drivers of Rb1 tumorigenesis and mechanisms of tumor resistance have afforded opportunities to explore novel targets such as the MDMX-p53 pathway (nutlin-3), histone deacetylase inhibitors, spleen tyrosine kinase inhibitors, and genetic and immune modulatory drugs. In this review, we discuss the limitations of current therapeutic strategies, candidate cellular pathways, current evidence for newer targeted drugs, and offer a look toward the future. Key Messages: Advances in the understanding of the molecular drivers of the RB pathway have provided opportunities to explore novel drugs with targeted effects, improved bioavailability, and reduced chemotoxicity.

This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1. DATA AVAILABILITY STATEMENT: The data that support the findings of this study are available from the authors upon reasonable request.

The exact mechanism of this result remains unclear, and further investigation is needed to elucidate the impact of XI-006 on TNBC and CRPC cell proliferation and migration. Our future directions include identifying the synergistic potential of combining MDM4/MDMX inhibitor XI-006 with other cancer therapies, assessing the impact of XI-006 on immune responses in co-culture studies, and testing therapeutic efficacy in vivo.

Overexpression of MDMX in HCT116 p53WT cells demonstrably confers remarkable resistance to MDMX inhibitor XI-006 at a 72-hour timepoint (IC50 of 104.75 uM in overexpressing cells versus 29.03 uM in WT), and treatment with oxaliplatin reveals both reduced basal and post-treatment expression of p53-upregulated modulator of apoptosis (PUMA). Further mechanistic workup of this phenomenon is underway, particularly with an emphasis on immuno-oncological therapeutic translations. Altogether, initial findings ultimately establish the need for further investigation into the mechanistic basis of MDMX-correlated clinical outcomes and the therapeutic potential of MDMX inhibition.

Verbenalin regulates ferroptosis and highlights the therapeutic potential of verbenalin and ferroptosis inhibition in reducing alcoholic steatohepatitis.

P1b, N=6, Terminated, Aileron Therapeutics, Inc. | N=26 --> 6 | Trial completion date: Jan 2024 --> Feb 2023 | Recruiting --> Terminated | Trial primary completion date: Sep 2023 --> Feb 2023; The study has been terminated early given that the first four patients enrolled have experienced Grade 4 neutropenia and alopecia after cycle 1 and as such failed to meet the primary endpoint and the main secondary endpoint.

We suggested that distinct haplotype patterns in different populations might affect the association between MDM4 SNPs and cancer risk. Thus, we propose to investigate some linkage SNPs in specific haplotypes to provide informative MDM4 markers for association studies with cancer.

Primary p53-wild-type AML blasts or isogenic cell lines were treated in vitro with graded doses of the MDM2 inhibitors Pevonedistat (PEVO) or Siremadlin, either added alone, or in combination with Ixazomib at pharmacokinetically-achievable dose ranges typical in patients. In addition, a combination of PEVO/Ixazomib was as effective for apoptosis as was Flt3 inhibitor among certain Flt3mutant primary AML blasts. A clinical test of this strategy is warranted in high-risk relapsed/refractory p53WT/p62SQSTM1-expressing AML.

P1b, N=26, Recruiting, Aileron Therapeutics, Inc.

Mechanistically, knockdown of BECN1 promotes the complex formation of MDM2 and MDMX, resulting in MDM2-dependent MDMX instability and RB stabilization. Our results demonstrate that nuclear Beclin 1 can promote cell cycle progression through modulation of the MDM2/X-RB pathway and suggest that Beclin 1 promotes CRC development by facilitating both cell cycle progression and autophagy.

P1b, N=35, Terminated, Aileron Therapeutics, Inc. | Active, not recruiting --> Terminated; With a favorable safety profile the difference between treatment groups for the primary composite endpoint was not sufficient to generate statistically significant results with the targeted sample size

Our findings suggest CEP-1347 is a novel inhibitor of MDM4 protein expression and as such activates p53 to inhibit the growth of cancer cells with wild-type p53, including retinoblastoma and glioblastoma.

Hesperidin can inhibit lung cancer by inhibiting the interaction between p53 and MDMX. Moreover, the combination of hesperidin and carboplatin can inhibit the migration and invasion of lung cancer cell lines through p53 upregulation, thereby increasing the antitumor effect of carboplatin.

All the FL118 analogues showed significant cytotoxic activities in vitro with IC values in the nanomolar range and were more potent than topotecan. It is noteworthy that 9c also demonstrated potent inhibition of drug-resistant tumor growth in NCI-H446/Irinotecan and NCI-H446/EP xenograft models, the tumor growth inhibition rates were 93.42% and 84.46%, respectively. Taken together, these findings indicated that compound 9c displays outstanding antitumor activity and drug-resistance in small-cell lung cancer both in vivo and in vitro, which could be worth further research as a novel anti-tumor drug against small-cell lung cancer.

We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.

To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.

P1b, N=35, Active, not recruiting, Aileron Therapeutics, Inc. | Recruiting --> Active, not recruiting | N=60 --> 35

P1, N=69, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2022 --> Jun 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

SE-LncRNA SENCR was upregulated in A549/DDP, which could promote cisplatin resistance and growth of NSCLC cell through upregulating FLI1 expression.

DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumour sensitivity to FL118. This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic. FL118 may act as a 'molecular glue degrader' to directly glue DDX5 and ubiquitination regulators together to degrade DDX5.

Moreover, XI-011 inhibited the growth of xenograft tumor in HeLa tumor-bearing mice, as well as enhanced the cytotoxic activity of cisplatin both in vitro and in vivo. Interestingly, MDMX co-locolized with E6AP and seems to be a novel binding partner of E6AP to promote p53 ubiquitination. In conclusion, this work revealed a novel mechanism of ubiquitin-dependent p53 degredation via MDMX-E6AP axis in cervical carcinogenesis, and offered the first evidence that MDMX could be a viable drug target for the treatment of cervical cancer.

Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of DNMT3A primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing DNMT3A R882X mutations.

In the present paper, we employ the MDM2-targeted small molecule Nutlin-3a (Nutlin) to disrupt the interaction of MDM2 and p53 in three different cancer cell lines: SJSA-1 (osteosarcoma), 93T449 (liposarcoma; both carrying amplified MDM2), and MCF7 (breast adenocarcinoma)...Depleting the MDM2 cofactor MDM4 in SJSA cells did not alter the velocity by that p53 was removed from promoters upon Nutlin washout. We conclude that MDM2 antagonizes p53 not only by covering its transactivation domain and by destabilization, but also by the rapid, ubiquitin-dependent termination of p53-chromatin interactions.

Disrupting MDMX function has potential to be beneficial for inhibition of breast cancer progression and metastasis. Supported by BCRF-20-011.

First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.