ArticleProceedings of the National Academy of Sciences of the United States of America2023
Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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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
8 citing papers in PubMed, 9 citations in OpenAlex.
- Structural basis for regulation of the proteasome 20S core particle by the Parkinsonism-associated proteins FBXO7 and PI31.bioRxiv : the preprint server for biology · 2026Article
- Magical moments in protease biology: proteasome autocatalytic activation and PI31-mediated inhibition.Trends in biochemical sciences · 2026Review
- UFMylation System: Biological Functions, Molecular Mechanisms, Diseases, and Drug Discovery.MedComm · 2025Review
- PI31 is a positive regulator of 20S immunoproteasome assembly.Journal of cell science · 2025Article
- Perturbation-Theory Machine Learning for Multi-Target Drug Discovery in Modern Anticancer Research.Current issues in molecular biology · 2025Review
- Evidence supporting a catalytic pentad mechanism for the proteasome and other N-terminal nucleophile enzymes.Nature communications · 2025Article
- Mechanisms and regulation of substrate degradation by the 26S proteasome.Nature reviews. Molecular cell biology · 2025Review
- Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib.Biochemistry and biophysics reports · 2024Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome's three active sites (β5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome's interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31's evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific β2 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound's cell permeability and establishing β2 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing β5 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.
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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.