ArticleCommunications chemistry2024
Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.
Article in Communications chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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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
9 citing papers in PubMed.
- From fusion partner to clinical practice: A treatment-oriented framework for transcription factor E3 (Cancer pathogenesis and therapy · 2026Review
- A Pyrazole-Based Small Molecule, KB3409, Restores Mitochondrial Function via VCP Activation and RCN2-Dependent CaAntioxidants (Basel, Switzerland) · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.Research square · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.bioRxiv : the preprint server for biology · 2026Article
- Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.Cell death & disease · 2026Article
- Cryo-EM structural analyses reveal plant-specific adaptations of the CDC48 unfoldase.Plant communications · 2026Article
- CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- 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
- A genome-scale drug discovery pipeline uncovers new therapeutic targets and a unique p97 allosteric binding site inbioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications.
Identifiers
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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.