ArticleThe Journal of biological chemistry2018
Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 49 citations in OpenAlex.
- Cereblon gene variants and clinical outcome in multiple myeloma patients treated with lenalidomide.Scientific reports · 2019Trial
- Understanding and addressing resistance to IMiDs immunomodulatory compounds in multiple myeloma.The FEBS journal · 2026Review
- Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design.Journal of chemical information and modeling · 2026Article
- Tuning the open-close equilibrium of Cereblon with small molecules influences protein degradation.bioRxiv : the preprint server for biology · 2025Article
- Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules.ACS central science · 2025Article
- Discovery of Dual BCL-xL/BCL-w Degraders by Exploiting the Bis(sulfonyl)benzene Ring of ABT-263 as a Linkage Vector.Journal of medicinal chemistry · 2025Article
- Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.Communications chemistry · 2025Review
- Thalidomide-induced limb malformations: an update and reevaluation.Archives of toxicology · 2025Review
- Targeting Ikaros and Aiolos with pomalidomide fails to reactivate or induce apoptosis of the latent HIV reservoir.Journal of virology · 2025Article
- Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders.Nature communications · 2024Article
- Continuous evolution of compact protein degradation tags regulated by selective molecular glues.Science (New York, N.Y.) · 2024Article
- Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System.Molecules (Basel, Switzerland) · 2022Review
- Article
- CDK9 inhibitors in multiple myeloma: a review of progress and perspectives.Medical oncology (Northwood, London, England) · 2022Review
- Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance.Frontiers in oncology · 2022Review
- Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91.Journal of medicinal chemistry · 2021Article
- Sweet and Blind Spots in E3 Ligase Ligand Space Revealed by a Thermophoresis-Based Assay.ACS medicinal chemistry letters · 2021Article
- Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Role of cereblon in angiogenesis and in mediating the antiangiogenic activity of immunomodulatory drugs.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders.Chemical science · 2020Article
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 2 countries.
Funding
Abstract
Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3 ubiquitin ligase in human cells but not in mouse cells, suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBN's activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBN's nonprimate sequence variations. With a series of recombinant thalidomide-binding domain (TBD) proteins, we show that CRBN sequence variants retain their drug-binding properties to both classical immunomodulatory drugs and dBET1, a chemical compound and targeting ligand designed to degrade bromodomain-containing 4 (BRD4) via a CRBN-dependent mechanism. We further show that dBET1 stimulates CRBN's E3 ubiquitin-conjugating function and degrades BRD4 in both mouse and human cells. This insight paves the way for studies of CRBN-dependent proteasome-targeting molecules in nonprimate models and provides a new understanding of CRBN's substrate-recruiting function.
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Registered trials
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