ArticleProceedings of the National Academy of Sciences of the United States of America2016
2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers, 1 of them a synthesis that pooled it.
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Who cites it
79 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- Article
- Revisiting tumor immunogenicity through the lens of mutant p53: Implications for cancer immunotherapy.Apoptosis : an international journal on programmed cell death · 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
- Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.Cellular & molecular biology letters · 2026Review
- Tunable Aromatic Sulfoxides and Sulfones as Cysteine-Targeting Warheads: Exploring the Structure-Reactivity Relationship.Journal of medicinal chemistry · 2026Article
- Restoration of the Y220C p53 Full-Length Mutant by PK11000: a Molecular Dynamics Study of an Intrinsically Disordered Protein.ACS omega · 2026Article
- 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
- PK11007 Covalently Inhibits Thioredoxin Reductase 1 to Induce Oxidative Stress and Autophagy Impairment in NSCLC Cells.Antioxidants (Basel, Switzerland) · 2025Article
- Network Theory Analysis of Allosteric Drug-Rescue Mechanisms in the Tumor Suppressor Protein p53 Y220C Mutant.International journal of molecular sciences · 2025Article
- MD Multi-Sector Selector: Recursive Extraction and Refinement of Molecular Dynamics Based Sectors Yields Two Sectors in p53 Tumor Suppressor Protein.The journal of physical chemistry. B · 2025Article
- SDrug design, development and therapy · 2025Article
- Covalent Fragments Acting as Tyrosine Mimics for Mutant p53-Y220C Rescue by Nucleophilic Aromatic Substitution.ACS pharmacology & translational science · 2024Article
- From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy.Biomarker research · 2024Review
- Covalent Modification of p53 by (ACS pharmacology & translational science · 2024Article
- Navigating the complexity of p53-DNA binding: implications for cancer therapy.Biophysical reviews · 2024Review
- Targeting mutant p53 with arsenic trioxide: A preclinical study focusing on triple negative breast cancer.Translational oncology · 2024Article
- APR-246 as a radiosensitization strategy for mutant p53 cancers treated with alpha-particles-based radiotherapy.Cell death & disease · 2024Article
- Anticancer therapeutic strategies for targeting mutant p53-Y220C.Journal of biomedical research · 2024Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 3 institutions in 2 countries.
Funding
Abstract
The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1(MET)(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.
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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.