Cereblon (CRBN)
Cereblon (CRBN) is an intracellular multifunctional protein that functions as a component of an E3 ubiquitin ligase system and cooperates with other elements of the ubiquitin–proteasome pathway.
Cereblon (CRBN) is an intracellular multifunctional protein that functions as a component of an E3 ubiquitin ligase system and cooperates with other elements of the ubiquitin–proteasome pathway. Its biological importance derives in part from its ability to bind immunomodulatory drugs such as lenalidomide and to participate in the selective ubiquitination and proteasomal degradation of recruited proteins. 42101529May42627009Aug
CRBN has become a central pharmacological target for targeted protein degradation. Cereblon-recruiting molecular glue degraders can promote degradation of proteins such as IKZF1, IKZF3, GSPT1, GSPT2, CK1α, and SCD, whereas CRBN-recruiting proteolysis-targeting chimeras (PROTACs) use a bifunctional design to bring CRBN-containing ligase machinery into proximity with a selected target. These mechanisms have been investigated in multiple myeloma, immune-cell regulation, cancer therapy, and drug-delivery development. 42118707May42149616May42051197Apr
- Discovery of Highly Potent and Selective, Orally Bioavailable BTK-Targeting PROTACs Featuring Novel CRBN-Binding Warheads. PMID 42720469
Where the papers sit
10 papers study cereblon (crbn) directly. The themes below are drawn from those 10.
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Cereblon Drug Development : Work spans CRBN binding-site characterization, PROTAC and prodrug design, radiolabeled lenalidomide derivatives, and biomarker evaluation in sepsis, without a single shared biological direction. 5 papers · 50%
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Molecular Glue Degraders : Molecular glue research is advancing from scalable discovery toward safety assessment and endocrine-resistant cancer treatment, including ERα degradation through HSP27-associated E3 ligase recruitment. 3 papers · 30%
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Targeted Protein Degradation : CRBN-recruiting degraders are expanding from BTK-directed designs toward immune modulation, with IKZF1/3 degradation by mezigdomide restoring cytokine production and reversing T-cell exhaustion. 2 papers · 20%
Recent Findings on Cereblon (CRBN)
Cereblon Drug Development: The thalidomide-binding domain of human cereblon provides a structural basis for ligand-binding and PROTAC optimization, with NMR resonance assignments confirming lenalidomide interaction 42101529May. C13p enhances hFAAH–CRBN protein-protein interactions and supports stepwise assembly, with hFAAH dissociation and candidate ubiquitination sites defining a cyclic recruitment mechanism 42333818Jun. CRBN-recruiting PROTAC prodrugs use triazole quaternization, tertiary-amine alkylation, or hydroxyl linkers to control self-immolative release, while cellular potency follows designed cleavage rates 42554619Aug. Chelator-free [99mTc(η6-lena)2]+ enables lenalidomide radiolabeling, whereas bioorganometallic modification reduces CRBN binding and produces rapid blood clearance with predominant renal excretion 42627009Aug. The paediatric sepsis protocol will test whether CRBN mRNA and protein levels predict 28-day mortality, organ failure, inflammation, and intensive-care outcomes 42613111Aug.
Molecular Glue Degraders: VI-10h degrades ERα in endocrine-resistant breast cancer by recruiting HSP27 as a non-canonical E3 ligase adaptor and forming an ERα–HSP27–RING1 complex, with greater xenograft activity than fulvestrant 42189698May. A scalable direct-to-biology platform generates more than 1,000 CRBN-centric molecules and identifies selective GSPT1 or CK1α degraders alongside a multi-target degrader 42149616May. These mechanisms broaden molecular glue degrader discovery beyond a single degradation model, while carcinogenicity assessment must weigh E3 ligase biology alongside the primary target 42051197Apr. Drug developers are therefore pairing scalable discovery with mechanistic validation and modified weight-of-evidence approaches, especially because early-generation cereblon molecular glue degraders show limited translatability 42051197Apr.
Targeted Protein Degradation: CRBN-recruiting BTK PROTACs use novel binding warheads to degrade wild-type and mutated BTK without concomitant IKZF1, IKZF3, or GSPT1 degradation; lead compounds show oral activity in malignant B cells and mice 42720469Sep. Mezigdomide instead deliberately degrades IKZF1 and IKZF3, reducing exhaustion-related markers, restoring proinflammatory cytokine expression, and enhancing alnuctamab-mediated target-cell killing 42118707May. These studies establish contrasting selectivity strategies: BTK degraders restrict CRBN-neosubstrate activity, whereas mezigdomide exploits it to reverse T-cell exhaustion. The field is consequently extending CRBN-based degradation from kinase-directed oncology toward immune modulation and combination treatment with T-cell engagers 42720469Sep42118707May.
Written from 10 PubMed abstracts, each one cited by PMID above. Published: 2026-08-29. Last written: 2026-09-11 by GPT. Drafted by language models from published abstracts; not medical advice.