ArticleDrug design, development and therapy2025
S
Article in Drug design, development and therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
5 citing papers in PubMed.
- Article
- Covalent Targeting and Thermostabilization of Oncogenic R280K and R273H Mutants p53 by Small Molecule RVJB59.ChemMedChem · 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
- False Friends in Fluorescence - Simple HPLC Evaluation of False Positive Fragment Hits in a DiFMUP Assay for Protein Tyrosine Phosphatase 1B.Drug design, development and therapy · 2026Article
- Characterization of the Second-Generation Covalent Fragment Library (CovLib Gen2): Thiol Reactivity Profiling and p53-Y220C Rescue.Drug design, development and therapy · 2026Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Purpose: The tumor suppressor p53 is most commonly mutated in human cancer. The structural mutant in the β-sandwich of the protein, p53-Y220C, is the ninth most common p53 mutant. The p53-Y220C mutant has a solvent-accessible hydrophobic pocket, leading to thermal destabilization of the protein. Screening of our covalent fragment library (CovLib) revealed the highly reactive pyrazine derivatives SN006 and SN007, which arylate among other cysteines in p53, the mutation-generated Cys220. Herein, comprehensive structure-activity relationship (SAR) studies of these intrinsically reactive CovLib hits were performed, aiming to identify improved stabilizers for p53-Y220C, with a more balanced reactivity profile, diverse binding modes and a better potential for chemical optimization. Methods: The compounds were screened for enhanced stabilization of p53 wild type and its mutants using differential scanning fluorimetry (DSF). To confirm covalent modification, intact mass spectrometry was performed. Thiol reactivity profiles were determined using a standardized Glutathione-modifying (GSH) assay. The binding modes of the identified hits and covalent modification of Cys220 were elucidated by X-ray crystallography. Moreover, the influence of the hits on the DNA-binding affinity of full-length p53 was investigated employing a fluorescence polarization assay (FPA). Results and Conclusion: The promising pyrazine derivatives SN006/7-3, SN006/7-8, and SN006/7-9 were identified, occupying different subsites of the Y220C binding pocket. The compound SN006/7-8 substantially stabilized the thermosensitive cancer mutant Y220C by up to 5.0 °C, representing a strong enhancement over SN006 (1.8 °C) and SN007 (2.0 °C).
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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.