ArticleFrontiers in molecular biosciences2022
Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule.
Article in Frontiers in molecular biosciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed, 8 citations in OpenAlex.
- Harnessing p53 for Proximity Killing.International journal of molecular sciences · 2026Review
- RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma.Cellular & molecular biology letters · 2026Review
- An integrated multiscale computational study of nephrotoxicity mechanism of citrinin and its metabolites (CIMs)：density functional theory, network toxicology, and molecular dynamics simulation.Mycotoxin research · 2025Article
- Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis).Cell death & disease · 2024Article
- Design, Synthesis, andAnti-cancer agents in medicinal chemistry · 2024Article
- Decreased DNA Damage and Improved p53 Specificity of RITA Analogs.Molecular cancer therapeutics · 2022Article
- The Therapeutic Potential of the Restoration of the p53 Protein Family Members in theInternational journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 4 countries.
Funding
Abstract
Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.