Molecular investigation of the dual inhibition mechanism for targeted P53 regulator MDM2/MDMX inhibitors

Zhao, Xiaoyu; Xiong, Danyang; Luo, Song; Duan, Lili

doi:10.1039/d2cp01780f

Cited by 3 publications

(4 citation statements)

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“…78 Moreover, MDMX, a homolog of MDM2, has been shown to stabilize MDM2, and formations of MDM2/ MDMX dimers augment p53 ubiquitination. 76,[86][87][88] As studies suggest that MDMX too is overexpressed in a number of cancers, dual inhibition of MDM2 and MDMX may be necessary for efficacious liberation of p53. 89 ALRN-6924, an α-helical peptide that inhibits both MDM2 and MDMX, was investigated in a phase I study in patients with solid tumors or lymphomas; evidence of tolerability and activity was demonstrated, resulting in 4.9% complete response, 4.9% partial response, and 48.8% stable disease.…”

Section: Regulators Of Transcription Factor Activitymentioning

confidence: 99%

“…Although inhibiting MDM2 is a viable therapeutic strategy for cancers with wild-type p53, the remaining 50% of cancers are hindered by p53 mutations; this illustrates a prominent limitation of this approach 78 . Moreover, MDMX, a homolog of MDM2, has been shown to stabilize MDM2, and formations of MDM2/MDMX dimers augment p53 ubiquitination 76,86–88 . As studies suggest that MDMX too is overexpressed in a number of cancers, dual inhibition of MDM2 and MDMX may be necessary for efficacious liberation of p53 89 .…”

Section: Targeting Protein-protein Interactionsmentioning

confidence: 99%

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Transcription Factors and Cancer

2023

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Cancer is defined by the presence of uncontrollable cell growth, whereby improper proliferative signaling has overcome regulation by cellular mechanisms. Transcription factors are uniquely situated at the helm of signaling, merging extracellular stimuli with intracellular responses. Therefore, this class of proteins plays a pivotal role in coordinating the correct gene expression levels for maintaining normal cellular functions. Dysregulation of transcription factor activity unsurprisingly drives tumorigenesis and oncogenic transformation. Although this imparts considerable therapeutic potential to targeting transcription factors, their lack of enzymatic activity renders intervention challenging and has contributed to a sense that transcription factors are “undruggable.” Yet, enduring efforts to elucidate strategies for targeting transcription factors as well as a deeper understanding of their interactions with binding partners have led to advancements that are emerging to counter this narrative. Here, we highlight some of these approaches, focusing primarily on therapeutics that have advanced to the clinic.

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Section: Regulators Of Transcription Factor Activitymentioning

confidence: 99%

Section: Targeting Protein-protein Interactionsmentioning

confidence: 99%

Transcription Factors and Cancer

2023

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“…Alanine scanning combined with the IE (ASIE) method utilized in this study addresses absolute errors and accurately assesses the entropic contribution of each residue, as its reliability has been extensively validated. 42,[46][47][48][49][50][51][52][53] In this study, we systematically investigated the origin of the binding differences in the R2R3-DNA system caused by four DNA methylations (5mC, 6m1A, 6m2A and 6mAA). Three rounds of molecular dynamics (MD) simulations were performed for each system to ensure sufficient sampling and identify stable conformations.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%