Academic Journal
Progress of structurally diverse cereblon (CRBN) ligands and their application in PROTAC degraders.
| Τίτλος: | Progress of structurally diverse cereblon (CRBN) ligands and their application in PROTAC degraders. |
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| Συγγραφείς: | Yang S; Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China., Zhang Y; Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China., Song X; Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China., Liu Q; Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China. Electronic address: liuqc21@nwu.edu.cn., Fan D; Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China; Engineering Research Center of Western Resource Innovation Medicine Green Manufacturing, Ministry of Education, School of Chemical Engineering, Northwest University, Xi'an 710069, China. Electronic address: fandaidi@nwu.edu.cn., Xu Y; Department of Pharmaceutical Engineering, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi'an 710069, China. Electronic address: xuying@nwu.edu.cn. |
| Πηγή: | Bioorganic chemistry [Bioorg Chem] 2026 Aug 15; Vol. 178, pp. 109968. Date of Electronic Publication: 2026 May 10. |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| Ιατρικοί όροι (MeSH): | Ubiquitin-Protein Ligases*/metabolism , Adaptor Proteins, Signal Transducing*/metabolism, Proteolysis/drug effects ; Ligands ; Humans ; Proteolysis Targeting Chimera ; Structure-Activity Relationship ; Molecular Structure ; Animals |
| Περίληψη: | Protein degradation-targeting chimeras (PROTACs) degrade target proteins by hijacking the ubiquitin-proteasome pathway, and their unique mechanism of action has attracted great attention from the scientific community over the past decade. In recent years, the field has achieved significant advancements, mainly due to the advent of various E3 ligase ligands and their prevalent application in the design of PROTACs. To date, more than ten E3 ligases have been exploited for the development of PROTACs. Notably, recruiting cereblon (CRBN) represents one of the most widely reported strategies in PROTAC design, attributed to the widespread expression across various tissues of CRBN and the favorable drug-like characteristics and synthetic accessibility of classical CRBN ligands, immunomodulatory imide drugs (IMiDs). Nevertheless, IMiDs face significant challenges, including inducing neo-substrate degradation, inherent racemization, and readily undergoing hydrolysis. In recent years, numerous structurally diverse CRBN ligands with enhanced selectivity and stability have been synthesized for the development of PROTACs. This review provides a systematic overview of the development of CRBN ligands with distinct structural scaffolds reported in peer-reviewed literature, focusing on activity optimization processes, structure-activity relationship investigations, and their practical applications in PROTACs design. Additionally, we further summarize conditionally activated CRBN-based PROTACs with reduced off-target toxicity. The aim is to offer both practical insights and innovative perspectives for future investigations in this fast-evolving field. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Cereblon (CRBN); E3 ligase Ligands; Protein degradation; Protein degradation targeting chimeras (PROTACs); Ubiquitin proteasome system |
| Substance Nomenclature: | 0 (Ligands) 0 (Proteolysis Targeting Chimera) EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (CRBN protein, human) 0 (Adaptor Proteins, Signal Transducing) |
| Entry Date(s): | Date Created: 20260514 Date Completed: 20260716 Latest Revision: 20260716 |
| Update Code: | 20260717 |
| DOI: | 10.1016/j.bioorg.2026.109968 |
| PMID: | 42134201 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2120 |
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| DOI: | 10.1016/j.bioorg.2026.109968 |