ArticleJournal of biomolecular NMR2004
NMR structure of a complex between MDM2 and a small molecule inhibitor.
Article in Journal of biomolecular NMR, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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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
19 citing papers in PubMed, 74 citations in OpenAlex.
- Synthesis and Biological Evaluation of Novel Synthetic Indolone Derivatives as Anti-Tumor Agents Targeting p53-MDM2 and p53-MDMX.Molecules (Basel, Switzerland) · 2022Article
- Ligand-Based and Docking-Based Virtual Screening of MDM2 Inhibitors as Potent Anticancer Agents.Computational and mathematical methods in medicine · 2021Article
- Recent Small-Molecule Inhibitors of the p53-MDM2 Protein-Protein Interaction.Molecules (Basel, Switzerland) · 2020Review
- Review
- Monitoring Ligand-Induced Protein Ordering in Drug Discovery.Journal of molecular biology · 2016Article
- Ligand binding mode prediction by docking: mdm2/mdmx inhibitors as a case study.Journal of chemical information and modeling · 2014Article
- On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein.Cell cycle (Georgetown, Tex.) · 2013Article
- Benzimidazole-2-one: a novel anchoring principle for antagonizing p53-Mdm2.Bioorganic & medicinal chemistry · 2013Article
- Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity.Expert reviews in molecular medicine · 2012Review
- Chemistry and biology of multicomponent reactions.Chemical reviews · 2012Review
- Article
- Article
- P53 mdm2 inhibitors.Current pharmaceutical design · 2012Review
- The p53-MDM2/MDMX axis - A chemotype perspective.MedChemComm · 2011Article
- Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists.Angewandte Chemie (International ed. in English) · 2010Article
- What induces pocket openings on protein surface patches involved in protein-protein interactions?Journal of computer-aided molecular design · 2009Article
- Therapeutic considerations for Mdm2: not just a one trick pony.Expert opinion on drug discovery · 2008Article
- Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53-HDM2 Protein-Protein Interaction.International journal of peptide research and therapeutics · 2006Article
- Targeting protein-protein interactions for cancer therapy.Journal of molecular medicine (Berlin, Germany) · 2005Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
MDM2 is a regulator of cell growth processes that acts by binding to the tumor suppressor protein p53 and ultimately restraining its activity. While inactivation of p53 by mutation is commonly observed in human cancers, a substantial percentage of tumors express wild type p53. In many of these cases, MDM2 is overexpressed, and it is believed that suppression of MDM2 activity could yield therapeutic benefits. Therefore, we have been focusing on the p53-MDM2 interaction as the basis of a drug discovery program and have been able to develop a series of small molecule inhibitors. We herein report a high resolution NMR structure of a complex between the p53-binding domain of MDM2 and one of these inhibitors. The form of MDM2 utilized was an engineered hybrid between the human and Xenopus sequences, which provided a favorable combination of relevancy and stability. The inhibitor is found to bind in the same site as does a highly potent peptide fragment of p53. The inhibitor is able to successfully mimic the peptide by duplicating interactions in three subpockets normally made by amino acid sidechains, and by utilizing a scaffold that presents substituents with rigidity and spatial orientation comparable to that provided by the alpha helical backbone of the peptide. The structure also suggests opportunities for modifying the inhibitor to increase its potency.
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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.