ArticleLeukemia2019
Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma.
Article in Leukemia, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 43 citations in OpenAlex.
- Two Mechanisms One Molecule: Developing a 'Truly' Bifunctional Degrader Targeting Rpn13 and CRBN.Journal of the American Chemical Society · 2026Article
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- Proteasome activity maintains cell-type-specific gene expression.Cell reports · 2026Article
- SCaN: A Screening and Characterization Platform for Nanosuspensions Enables In Vivo Delivery of a Crystalline hRpn13ACS pharmacology & translational science · 2026Article
- A propensity score matching study on clinical characteristics and risk factors of herpes zoster in malignant tumor.Frontiers in oncology · 2026Article
- [Research and Therapeutic Advances of 26S Proteasome Subunit in Non-small Cell Lung Cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Review
- Targeted protein degradation in hematologic malignancies: clinical progression towards novel therapeutics.Biomarker research · 2024Review
- Article
- TET2 stabilized by deubiquitinase USP21 ameliorates cigarette smoke-induced apoptosis in airway epithelial cells.iScience · 2024Article
- Article
- The prognostic value of 19S ATPase proteasome subunits in acute myeloid leukemia and other forms of cancer.Frontiers in medicine · 2023Article
- Immunogenic cell death triggered by impaired deubiquitination in multiple myeloma relies on dysregulated type I interferon signaling.Frontiers in immunology · 2023Article
- 19S Proteasome Subunits as Oncogenes and Prognostic Biomarkers in FLT3-Mutated Acute Myeloid Leukemia (AML).International journal of molecular sciences · 2022Article
- Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2.FEBS letters · 2022Article
- Proteolysis-targeting chimeras (PROTACs) in cancer therapy.Molecular cancer · 2022Review
- Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.Nature communications · 2021Article
- Review
- The PROTACtable genome.Nature reviews. Drug discovery · 2021Review
- Advancing targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2021Review
- Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Proteasome inhibition is an effective treatment for multiple myeloma (MM); however, targeting different components of the ubiquitin-proteasome system (UPS) remains elusive. Our RNA-interference studies identified proteasome-associated ubiquitin-receptor Rpn13 as a mediator of MM cell growth and survival. Here, we developed the first degrader of Rpn13, WL40, using a small-molecule-induced targeted protein degradation strategy to selectively degrade this component of the UPS. WL40 was synthesized by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide. We show that WL40 binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13, and is therefore first-in-class in exploiting a covalent inhibitor for the development of degraders. Biochemical and cellular studies show that WL40-induced Rpn13 degradation is both CRBN E3 ligase- and Rpn13-dependent. Importantly, WL40 decreases viability in MM cell lines and patient MM cells, even those resistant to bortezomib. Mechanistically, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling. In animal model studies, WL40 inhibits xenografted human MM cell growth and prolongs survival. Overall, our data show the development of the first UbR Rpn13 degrader with potent anti-MM activity, and provide proof of principle for the development of degraders targeting components of the UPS for therapeutic application.
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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.