ArticleACS chemical biology2020
Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm.
Article in ACS chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Article
- Structural basis for T-cell receptor recognition of p53Acta crystallographica. Section D, Structural biology · 2026Article
- 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
- Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs.Nature chemical biology · 2026Article
- Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt.Cell death & disease · 2026Article
- Evolution of Engineered ADAR-Based RNA Editing Systems.International journal of molecular sciences · 2026Review
- Characterization of the Second-Generation Covalent Fragment Library (CovLib Gen2): Thiol Reactivity Profiling and p53-Y220C Rescue.Drug design, development and therapy · 2026Article
- Profiling of Protein-Coding Missense Mutations in Mendelian Rare Diseases: Clues from Structural Bioinformatics.International journal of molecular sciences · 2025Article
- Polyphenols fromPharmaceutics · 2025Article
- Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations.Nature genetics · 2025Article
- Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.ACS pharmacology & translational science · 2024Article
- Emerging Tumor-Agnostic Molecular Targets.Molecular cancer therapeutics · 2024Review
- Bioinformatic Characterization of the Functional and Structural Effect of Single Nucleotide Mutations in Patients with High-Grade Glioma.Biomedicines · 2024Article
- Functional Investigations of p53 Acetylation Enabled by Heterobifunctional Molecules.ACS chemical biology · 2024Article
- Design, Synthesis, and Evaluation of p53Y220C Acetylation Targeting Chimeras (AceTACs).Journal of medicinal chemistry · 2024Article
- Targeting apoptotic pathways for cancer therapy.The Journal of clinical investigation · 2024Review
- Structural basis of p53 inactivation by cavity-creating cancer mutations and its implications for the development of mutant p53 reactivators.Cell death & disease · 2024Article
- Comparison ofBlood neoplasia · 2024Article
- Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability, and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N, and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions. A high-resolution crystal structure of the Y220S mutant DBD revealed a mutation-induced surface crevice similar to that of Y220C, whereas the corresponding pocket's accessibility to small molecules was blocked in the structure of the Y220H mutant. Accordingly, a series of carbazole-based small molecules, designed for stabilizing the Y220C mutant, also bound to and stabilized the folded state of the Y220S mutant, albeit with varying affinities due to structural differences in the binding pocket of the two mutants. Some of the compounds also bound to and stabilized the Y220N mutant, but not the Y220H mutant. Our data validate the Y220S and Y220N mutants as druggable targets and provide a framework for the design of Y220S or Y220N-specific compounds as well as compounds with dual Y220C/Y220S specificity for use in personalized cancer 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.