ArticleProceedings of the National Academy of Sciences of the United States of America2008
Targeted rescue of a destabilized mutant of p53 by an in silico screened drug.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 229 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
229 citing papers in PubMed, 1 synthesis or guideline pooled it, 370 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Article
- Biological Activities and Phytochemical Composition of Arum rupicola var. rupicola: An In Vitro and In Silico Study.Chemistry & biodiversity · 2026Article
- Structure-based identification of small-molecule stabilizers targeting mutant TP53 (Y220C) in breast cancer: a pharmacophore modeling, molecular docking and dynamics study.Journal, genetic engineering & biotechnology · 2026Article
- Revisiting tumor immunogenicity through the lens of mutant p53: Implications for cancer immunotherapy.Apoptosis : an international journal on programmed cell death · 2026Review
- PhiKan 083 Inhibits MYCN Expression in Liver Cancer Cells Independent of p53 Pathways.ACS pharmacology & translational science · 2026Article
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- p53 mutation-associated prognosis across cancer types underlines hematological malignancy as an applicable cancer type to p53-rescue therapy.Fundamental research · 2026Article
- Systems Biology and Atomistic Simulations Reveal Multi-Target Modulation of Alzheimer's Disease and Type 2 Diabetes byInternational journal of molecular sciences · 2026Article
- Targeting p53 in Cancer: Functional States, Therapeutic Strategies, and Clinical Progress.Cancers · 2026Review
- Covalent drug rescue of multiple p53 mutants by stabilizing vinyl sulfone fragments hints to a specific refolding mechanism for R282W.Protein science : a publication of the Protein Society · 2026Article
- Activating p53Nature communications · 2026Article
- Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs.Nature chemical biology · 2026Article
- Hijacking mutant p53 abundance.Nature chemical biology · 2026Article
- p53: from understanding its structure to advances in therapeutic targeting.Signal transduction and targeted therapy · 2026Review
- Unraveling the role ofHemaSphere · 2026Review
- Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt.Cell death & disease · 2026Article
- Hidden Interactions: Quantum Perspectives in Drug Design.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Characterization of the Second-Generation Covalent Fragment Library (CovLib Gen2): Thiol Reactivity Profiling and p53-Y220C Rescue.Drug design, development and therapy · 2026Article
- Cellular activity upregulation of the thermolabile p53 cancer mutant Y220C by small molecule indazole derivatives.Cell death discovery · 2025Article
169 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The tumor suppressor p53 is mutationally inactivated in approximately 50% of human cancers. Approximately one-third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilize them could be effective anticancer drugs. The mutation Y220C, which occurs in approximately 75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in silico analysis of the crystal structure using virtual screening and rational drug design. One of them, a carbazole derivative (PhiKan083), binds to the cavity with a dissociation constant of approximately 150 muM. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the protein-PhiKan083 complex at 1.5-A resolution. The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimization. The Y220C mutant is an excellent "druggable" target for developing and testing novel anticancer drugs based on protein stabilization. We point out some general principles in relationships between binding constants, raising of melting temperatures, and increase of protein half-lives by stabilizing ligands.
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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.