ArticleCell research2018
Small molecule inhibitors reveal allosteric regulation of USP14 via steric blockade.
Article in Cell research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 123 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Emerging regulatory model of Ubiquitin-Specific Proteases 14 in cancer: from canonical oncogenesis to TME modulation, therapeutic resistance, and non-canonical activities.Journal of translational medicine · 2026Review
- Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome.Nature communications · 2026Article
- Novel Small-Molecule Analogues of IU1 Ameliorate Amyloid-β Mediated Toxicity in Alzheimer's Disease Cell and Worm Models.International journal of molecular sciences · 2026Article
- Deubiquitinating enzymes at the crossroads of blood-brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions.Tissue barriers · 2026Review
- Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.Frontiers in cellular neuroscience · 2026Review
- Modulation of the tumor microenvironment by the ubiquitin-proteasome system in colorectal cancer.Journal of translational medicine · 2025Review
- Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.Nature structural & molecular biology · 2025Article
- Beyond Docking: A Multitier Computational Pipeline for USP7 Inhibitor Optimization.ChemMedChem · 2025Article
- AKT and DUBs: a bidirectional relationship.Cellular & molecular biology letters · 2025Review
- Targeting the TRIM14/USP14 axis enhances radiotherapy efficacy by inducing GPX4 degradation and disrupting ferroptotic defense in HCC.Cell death & disease · 2025Article
- Targeted Degradation of Histone Deacetylases via Bypassing E3 Ligase Targeting Chimeras (BYETACs).ACS medicinal chemistry letters · 2025Article
- Structure-based discovery of novel non-covalent small molecule inhibitors of USP30.Journal of computer-aided molecular design · 2025Article
- Dynamic networks connect the USP14 active site region with the proteasome interaction surface.Protein science : a publication of the Protein Society · 2025Article
- Ubiquitin-Specific Protease Inhibitors for Cancer Therapy: Recent Advances and Future Prospects.Biomolecules · 2025Review
- Molecular targeting of the deubiquitinase USP14 to circumvent cisplatin resistance in ovarian carcinoma and identification of novel inhibitors.Cancer drug resistance (Alhambra, Calif.) · 2025Article
- USP14 inhibition enhances Parkin-independent mitophagy in iNeurons.Pharmacological research · 2024Article
- DUBs in Alzheimer's disease: mechanisms and therapeutic implications.Cell death discovery · 2024Review
- USP36 promotes colorectal cancer progression through inhibition of p53 signaling pathway via stabilizing RBM28.Oncogene · 2024Article
- Review
7 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ubiquitin system is important for drug discovery, and the discovery of selective small-molecule inhibitors of deubiquitinating enzymes (DUBs) remains an active yet extremely challenging task. With a few exceptions, previously developed inhibitors have been found to bind the evolutionarily conserved catalytic centers of DUBs, resulting in poor selectivity. The small molecule IU1 was the first-ever specific inhibitor identified and exhibited surprisingly excellent selectivity for USP14 over other DUBs. However, the molecular mechanism for this selectivity was elusive. Herein, we report the high-resolution co-crystal structures of the catalytic domain of USP14 bound to IU1 and three IU1 derivatives. All the structures of these complexes indicate that IU1 and its analogs bind to a previously unknown steric binding site in USP14, thus blocking the access of the C-terminus of ubiquitin to the active site of USP14 and abrogating USP14 activity. Importantly, this steric site in USP14 is very unique, as suggested by structural alignments of USP14 with several known DUB X-ray structures. These results, in conjunction with biochemical characterization, indicate a coherent steric blockade mechanism for USP14 inhibition by compounds of the IU series. In light of the recent report of steric blockade of USP7 by FT671, this work suggests a potential generally applicable allosteric mechanism for the regulation of DUBs via steric blockade, as showcased by our discovery of IU1-248 which is 10-fold more potent than IU1.
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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.