ArticleNature communications2022
Leveraging the multivalent p53 peptide-MdmX interaction to guide the improvement of small molecule inhibitors.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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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
8 citing papers in PubMed.
- Fundamentals and emerging frontiers in p53-targeted drug development.Biochemistry and biophysics reports · 2026Review
- Accurate site-specific folding via conditional diffusion based on AlphaFold3.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Discovery of a Phenylalanine-Derived Natural Compound as a Potential Dual Inhibitor of MDM2 and MDMX.ChemMedChem · 2025Article
- Accurate Site-specific Folding via Conditional Diffusion Based on Alphafold3.bioRxiv : the preprint server for biology · 2025Article
- Advancements inMolecules (Basel, Switzerland) · 2024Review
- Molecular mechanism of CCDC106 regulating the p53-Mdm2/MdmX signaling axis.Scientific reports · 2023Article
- Biology of Pellino1: a potential therapeutic target for inflammation in diseases and cancers.Frontiers in immunology · 2023Review
- The MDMX Acidic Domain Uses Allovalency to Bind Both p53 and MDMX.Journal of molecular biology · 2022Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Overexpressed Mdm2 and its 7homolog MdmX impair p53 activity in many cancers. Small molecules mimicking a p53 peptide can effectively inhibit Mdm2 but not MdmX. Here, we show a strategy for improving lead compounds for Mdm2 and MdmX inhibition based on the multivalency of the p53 peptide. Crystal structures of MdmX complexed with nutlin-3a, a strong Mdm2 inhibitor but a weak one for MdmX, reveal that nutlin-3a fits into the ligand binding pocket of MdmX mimicking the p53 peptide. However, due to distinct flexibility around the MdmX ligand binding pocket, the structures are missing many important intermolecular interactions that exist in the MdmX/p53 peptide and Mdm2/nultin-3a complexes. By targeting these flexible regions, we identify allosteric and additive fragments that enhance the binding affinity of nutlin-3a for MdmX, leading to potent Mdm2/MdmX inhibitors with anticancer activity. Our work provides a practical approach to drug design for signal transduction therapy.
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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.