ArticleNature chemical biology2013
Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death.
Article in Nature chemical biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 248 papers.
What it found
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The trial behind it
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Who cites it
248 citing papers in PubMed, 381 citations in OpenAlex.
- Targeting ribosome biogenesis.Nature chemical biology · 2026Article
- p97-mediated proteostasis is a checkpoint for late-stage thymocyte positive selection.Cellular & molecular immunology · 2026Article
- Valosin-containing protein counteracts ATP-driven dissolution of FUS condensates through its ATPase activity in vitro.FEBS letters · 2026Article
- Proteomic Analysis Reveals That P97 Inhibitors Induce Ferroptosis in Gastric Cancer AGS Cells.Pharmaceuticals (Basel, Switzerland) · 2026Article
- VPS4 and CHMP7 release centromeres from the nuclear envelope for post-mitotic positioning in daughter nuclei.bioRxiv : the preprint server for biology · 2026Article
- p97/VCP as a dual regulator of UPS and autophagy in ovarian cancer: a novel therapeutic target.Journal of molecular histology · 2026Article
- Development and Structural Characterization of UTE-156, a Covalent Inhibitor of the VCP/p97 AAA+ ATPase.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Pex6 and ubiquitination regulate topological remodeling of the peroxisomal membrane protein Pex14.The Journal of biological chemistry · 2026Article
- A conformation-dependent hydrophobic degron determines Rab9a-mediated vesicular trafficking.The Journal of biological chemistry · 2026Article
- Nuclear tau aggregates inhibit RNA export and form by secondary seeding from cytosolic tau aggregates.bioRxiv : the preprint server for biology · 2026Article
- A small molecule VDAC ligand inhibits ERAD and induces selective cancer cell death via disruption of calcium homeostasis.Nature communications · 2026Article
- Expanded use of benzamidines in the Groebke-Blackburn-Bienaymé synthesis of imidazoles and their biological evaluation.Beilstein journal of organic chemistry · 2026Article
- The Fanconi anemia pathway repairs colibactin-induced DNA interstrand cross-links.Nature communications · 2025Article
- Synthesis of 1,2,4-Triazole-3-Thiol Derivatives from Thiosemicarbazides and Carboxylic Acids Using Polyphosphate Ester.Molecules (Basel, Switzerland) · 2025Article
- A cytoplasmic motif in HLA-E that drives clathrin-mediated endocytosis and VCP-associated postendocytic trafficking.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives.Molecular cancer · 2025Review
- Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics.Cancers · 2025Review
- A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site inProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Small Molecule-Induced Alterations of Protein Polyubiquitination Revealed by Mass-Spectrometric Ubiquitome Analysis.Angewandte Chemie (International ed. in English) · 2025Article
188 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
24 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
VCP (also known as p97 or Cdc48p in yeast) is an AAA(+) ATPase regulating endoplasmic reticulum-associated degradation. After high-throughput screening, we developed compounds that inhibit VCP via different mechanisms, including covalent modification of an active site cysteine and a new allosteric mechanism. Using photoaffinity labeling, structural analysis and mutagenesis, we mapped the binding site of allosteric inhibitors to a region spanning the D1 and D2 domains of adjacent protomers encompassing elements important for nucleotide-state sensing and ATP hydrolysis. These compounds induced an increased affinity for nucleotides. Interference with nucleotide turnover in individual subunits and distortion of interprotomer communication cooperated to impair VCP enzymatic activity. Chemical expansion of this allosteric class identified NMS-873, the most potent and specific VCP inhibitor described to date, which activated the unfolded protein response, interfered with autophagy and induced cancer cell death. The consistent pattern of cancer cell killing by covalent and allosteric inhibitors provided critical validation of VCP as a cancer target.
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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.