Affinage

CRBN

Protein cereblon · UniProt Q96SW2

Length
442 aa
Mass
50.5 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRBN is the substrate-recognition receptor of the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, where it dictates which proteins are ubiquitinated for proteasomal destruction (PMID:25043012). CRBN possesses a defined pocket that enantioselectively binds thalidomide and immunomodulatory imide drugs (IMiDs); drug occupancy creates a composite drug-CRBN surface that simultaneously blocks endogenous substrate binding (e.g., MEIS2) and reprograms the ligase to recruit neosubstrates (PMID:25043012). Crystal structures show that this neosubstrate interface engages a shared structural degron — a β-hairpin/G-loop presented by the kinase N-lobe of CK1α or the zinc-finger domains of IKZF1/IKZF3 (PMID:24328678, PMID:26909574) — and proteome-wide screening established that diverse C2H2 zinc-finger proteins, including ZFP91, dock at this permissive surface through a common mode (PMID:30385546, PMID:28530236). The same drug-dependent recruitment extends to SALL4, ARID2, PLZF/ZBTB16 and additional targets accessed by cereblon modulators (PMID:32958952, PMID:34764413, PMID:32071327). Endogenous, drug-independent substrates are recognized through a distinct C-terminal cyclic imide degron installed on asparagine residues by PCMT1, which co-regulates metabolic enzymes such as glutamine synthetase with CRBN (PMID:41461925). Productive degradation of CRL4CRBN-ubiquitinated substrates requires the E2 enzymes UBE2D3 (monoubiquitin priming) and UBE2G1 (K48 chain elongation), CUL4 neddylation, and p97/VCP-mediated extraction, while USP15 deubiquitinates substrates to antagonize their turnover (PMID:28320958, PMID:30042095, PMID:34583995). Beyond its ligase function, CRBN ubiquitinates and controls trafficking of ion channels: it retains BK channels in the ER, with loss of CRL4A(CRBN) activity lowering seizure threshold in mice, and it promotes degradation of ClC-2 chloride channels (PMID:24845235, PMID:32466489). CRBN also acts as an HSP90 co-chaperone that counteracts AHA1 for transmembrane-client quality control (PMID:33571422), and negatively regulates AMPK through its N- and C-terminal regions independently of the IMiD pocket to sustain mTOR-dependent translation (PMID:24993823, PMID:34073624). A C-terminal truncation mutant that fails to support mTOR-dependent translation is linked to human mild mental retardation (PMID:24993823).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2013 High

    Established the first molecular consequence of CRBN engagement by IMiDs — that lenalidomide/pomalidomide redirect CRL4CRBN to destroy specific transcription factors — answering how these drugs exert immunomodulatory effects.

    Evidence Co-IP, ubiquitination assays, proteasome rescue, and in vivo human pharmacodynamic detection of Aiolos loss

    PMID:24328678

    Open questions at the time
    • Did not provide the structural basis of drug-induced recruitment
    • Endogenous substrate repertoire unaddressed
  2. 2014 High

    Defined CRBN as the substrate receptor of CRL4CRBN and showed atomically that IMiD binding both blocks an endogenous substrate (MEIS2) and recruits neosubstrates (IKZF1/3), unifying drug binding and substrate reprogramming.

    Evidence X-ray crystallography of DDB1-CRBN-IMiD complexes plus unbiased substrate screen and ubiquitination assays

    PMID:25043012

    Open questions at the time
    • Did not resolve a ternary drug-CRBN-neosubstrate structure
    • Scope of neosubstrate degron not generalized
  3. 2014 High

    Revealed CRBN ligase functions beyond IMiD biology — ubiquitination and ER retention of BK channels, and a drug-independent AMPK-mTOR translational role with a disease-linked truncation mutant.

    Evidence Mouse genetic models, electrophysiology, AMPK/mTOR readouts, and rescue with WT vs. patient mutant CRBN

    PMID:24845235 PMID:24993823

    Open questions at the time
    • AMPK regulation mechanism (which domain, direct vs. indirect) not defined at this stage
    • BK degron not characterized
  4. 2016 High

    Solved the ternary CRBN-lenalidomide-CK1α structure, showing CRBN and the drug jointly form the neosubstrate interface engaging a β-hairpin degron, explaining selective del(5q) MDS efficacy.

    Evidence 2.45 Å ternary crystal structure with in vitro binding and mutagenesis

    PMID:26909574

    Open questions at the time
    • Generality of the degron mode across other substrate classes untested here
  5. 2017 High

    Generalized the neosubstrate concept by identifying ZFP91 via unbiased proteomics and linking it to an IKZF-related zinc-finger degron, and established that p97/VCP extraction is required downstream of ubiquitination.

    Evidence pSILAC mass spectrometry, ZnF mutagenesis, and p97 inhibition/dominant-negative rescue across multiple substrates

    PMID:28320958 PMID:28530236

    Open questions at the time
    • E2 enzyme identities not yet defined
    • Mechanism of p97 substrate handoff unresolved
  6. 2018 High

    Systematized the degron rules by mapping the C2H2 zinc-finger degron space and defined the enzymatic machinery (UBE2D3 priming, UBE2G1 elongation, neddylation control) plus an in vivo CRBN residue (I391V/V388) sufficient to confer drug sensitivity and teratogenicity.

    Evidence Proteome-wide degradation screen with multiple ternary crystal structures; genome-wide CRISPR screen; knock-in mouse model

    PMID:30042095 PMID:30064974 PMID:30385546

    Open questions at the time
    • Endogenous physiological degron chemistry still unknown
    • How E2 selection is achieved mechanistically unresolved
  7. 2020 High

    Broadened the substrate landscape (SALL4, ARID2, PLK1, CDK4) and showed subcellular distribution of CRBN, via KPNB1-mediated nuclear import, governs which substrates can be degraded; linked SALL4 degradation directly to thalidomide teratogenicity.

    Evidence Engineered hiPSC point-mutant rescue, proteomics/Co-IP, KPNB1 knockdown with fractionation and degradation assays

    PMID:32071327 PMID:32132601 PMID:32728610 PMID:32958952

    Open questions at the time
    • Most neosubstrates validated in single-lab cell systems
    • Endogenous functions of these substrates under CRBN control incompletely mapped
  8. 2021 Medium

    Defined antagonists and non-ligase functions: USP15 reverses CRL4CRBN ubiquitination of substrates; CRBN acts as an HSP90 co-chaperone counteracting AHA1; and AMPK regulation was shown to operate independently of the IMiD pocket via N-/C-terminal regions.

    Evidence Deubiquitination/stability assays, reciprocal Co-IP and cell-surface proteomics, and domain-deletion AMPK binding/activity assays

    PMID:31620128 PMID:33571422 PMID:34073624 PMID:34583995

    Open questions at the time
    • Non-ligase functions largely single-lab
    • Structural basis of CRBN-HSP90 and CRBN-AMPK interactions undefined
  9. 2025 High

    Identified the endogenous degron chemistry — PCMT1 generates C-terminal cyclic imide degrons that CRBN recognizes — and demonstrated a homo-dimerization molecular-glue mechanism inducing CRBN self-degradation, plus high-resolution structures rationalizing clinical CRBN mutations.

    Evidence In vitro enzymatic reconstitution with cellular/in vivo validation (PCMT1); cryo-EM of CRBN homodimer; high-resolution DDB1-CRBN-lenalidomide crystallography with dynamic modeling

    PMID:39841463 PMID:41258141 PMID:41461925

    Open questions at the time
    • Full endogenous substrate repertoire defined by cyclic imide degron incomplete
    • Physiological role of CRBN self-degradation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRBN's diverse non-ligase activities (HSP90 co-chaperone, AMPK regulation, mitochondrial/autophagy control) are integrated with its CRL4 receptor function, and the full physiological substrate set defined by the PCMT1 cyclic imide degron, remain unresolved.
  • No unified structural/cellular model linking ligase and non-ligase roles
  • Endogenous substrate landscape not comprehensively mapped
  • Several low-confidence substrate/regulator findings (BAG3, MORF4L1, USP2) await independent validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0044183 protein folding chaperone 1
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
AHA1CUL4ADDB1HSP90KPNB1UBE2D3UBE2G1USP15
Complex memberships
CRBN-AHA1-HSP90 chaperone axisCRL4CRBN (CUL4-RBX1-DDB1-CRBN E3 ubiquitin ligase)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Crystal structures of DDB1-CRBN bound to thalidomide, lenalidomide, and pomalidomide establish that CRBN is the substrate receptor within the CRL4(CRBN) E3 ubiquitin ligase complex and that it enantioselectively binds IMiDs. IMiDs block endogenous substrates (MEIS2) from binding CRL4(CRBN) while simultaneously recruiting IKZF1/IKZF3 for ubiquitination and degradation. MEIS2 was identified as an endogenous substrate of CRL4(CRBN) by an unbiased screen. X-ray crystallography (DDB1-CRBN-IMiD co-crystal structures), unbiased substrate screen, ubiquitination assays Nature High 25043012
2013 Lenalidomide and pomalidomide induce interaction of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) with the CRL4(CRBN) E3 ubiquitin ligase, leading to their enhanced ubiquitination and cereblon-dependent proteasomal degradation in T lymphocytes, thereby relieving transcriptional repression of IL-2 and causing T cell activation. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, CRBN-dependent knockdown experiments, Aiolos degradation confirmed in human subjects administered lenalidomide British journal of haematology High 24328678
2016 Crystal structure (2.45 Å) of DDB1-CRBN bound to lenalidomide and CK1α shows that CRBN and lenalidomide jointly provide the binding interface for a CK1α β-hairpin loop in the kinase N-lobe; CK1α binding to CRL4(CRBN) is strictly drug-dependent, and IKZF1 uses a related binding mode, explaining selective lenalidomide efficacy in del(5q) MDS. X-ray crystallography (ternary complex), in vitro binding assays, mutagenesis Nature High 26909574
2018 Systematic screening of the human C2H2 zinc finger proteome identified 11 zinc finger degrons recruited to the drug-CRBN interface by thalidomide analogs; structural and functional characterization demonstrated that diverse C2H2 zinc finger domains use a shared binding mode at the permissive CRBN surface, and computational docking predicted >150 zinc fingers can bind the drug-CRBN complex in vitro. Proteome-wide degradation screen, X-ray crystallography of multiple zinc finger-drug-CRBN complexes, biochemical binding assays, computational docking, selective compound modifications Science High 30385546
2017 Pulse-chase SILAC mass spectrometry identified ZFP91 as an IMiD-dependent CRL4(CRBN) neosubstrate; ZFP91 harbors a zinc finger motif related to the IKZF1/3 ZnF that is critical for IMiD-dependent CRBN binding, and lenalidomide induces its ubiquitination and degradation. pSILAC mass spectrometry, Co-immunoprecipitation, ubiquitination assays, mutagenesis of ZnF motif Nature communications High 28530236
2017 p97/VCP is required for degradation of CRL4(CRBN)-ubiquitylated glutamine synthetase (GS) and all four known IMiD-dependent CRBN neosubstrates (IKZF1, IKZF3, CK1α, GSPT1), establishing an intimate functional link between the CRL4(CRBN) E3 ligase and the p97 extraction pathway. Cell-based ubiquitylation and degradation assays with p97 inhibitors and dominant-negative p97, rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 28320958
2014 CRL4A(CRBN) E3 ubiquitin ligase ubiquitinates BK (large conductance Ca2+- and voltage-activated K+) channels and retains them in the endoplasmic reticulum; inactivation of CRL4A(CRBN) releases deubiquitinated BK channels to the plasma membrane, markedly enhancing channel activity and lowering seizure threshold, causing epileptogenesis in mice. Co-immunoprecipitation, ubiquitination assays, subcellular fractionation/live imaging, electrophysiology, mouse genetic models (brain-specific CRL4A(CRBN) mutation), pharmacological BK channel blockade Nature communications High 24845235
2018 A single I391V amino acid substitution in mouse Crbn (corresponding to human V388) is sufficient to confer sensitivity to thalidomide derivative-induced degradation of Ikaros, Aiolos, Zfp91, and CK1α both in vitro and in vivo, and also recapitulates thalidomide-induced fetal loss in mice. Mouse knock-in model, in vitro and in vivo degradation assays, genetic epistasis (Trp53 knockout causing lenalidomide resistance) Blood High 30064974
2018 Genome-wide CRISPR-Cas9 screen identified UBE2D3 and UBE2G1 as E2 ubiquitin-conjugating enzymes with distinct roles in CRL4(CRBN)-mediated substrate ubiquitination: UBE2D3 primes targets via monoubiquitination while UBE2G1 extends K48-linked polyubiquitin chains. Loss of UBE2M or COP9 signalosome components alters CUL4A neddylation and impairs lenalidomide-dependent CRL4(CRBN) activity. Genome-wide CRISPR-Cas9 positive selection screen, IKZF3 degron reporter counterscreen, genetic validation with individual guide RNAs, neddylation assays Blood High 30042095
2020 ARID2, a subunit of the PBAF chromatin-remodeling complex, is a pomalidomide-induced neosubstrate of CRL4(CRBN); BRD7 (another PBAF subunit) is required for pomalidomide-induced ARID2 degradation, and ARID2 regulates transcription of pomalidomide target genes including MYC. Proteomic substrate identification, Co-immunoprecipitation, ubiquitination assays, CRBN-dependent degradation rescue experiments, transcriptional reporter assays Nature chemical biology High 32958952
2021 CRBN functions as a co-chaperone that specifically determines HSP90 chaperone activity toward transmembrane proteins by counteracting AHA1; IMiDs disrupt the CRBN-HSP90 interaction, impairing transmembrane protein quality control. LAT1/CD98hc was identified as a client of the CRBN-AHA1-HSP90 axis and a determinant of IMiD activity in multiple myeloma. Co-immunoprecipitation, cell surface proteomics, genetic knockdown/knockout experiments, functional assays in MM cells Molecular cell High 33571422
2021 USP15 deubiquitylase antagonizes CRL4(CRBN)-mediated ubiquitylation of the natural substrate glutamine synthetase (GS) and neosubstrates IKZF1, IKZF3, CK1α, RNF166, GSPT1, and BRD4, thereby preventing their degradation; USP15 is highly expressed in IMiD-resistant cells and its depletion sensitizes cells to lenalidomide. Ubiquitylation assays, protein stability assays, USP15 knockdown/overexpression, IMiD resistance cell models Proceedings of the National Academy of Sciences of the United States of America Medium 34583995
2021 PLZF/ZBTB16 and its leukemogenic fusion proteins (e.g., PLZF-RARα) are pomalidomide-dependent neosubstrates of CRL4(CRBN); pomalidomide treatment induces their ubiquitination and degradation via CRBN, leading to antiproliferation of leukemic cells expressing PLZF-RARα. Co-immunoprecipitation, ubiquitination assays, CRBN-dependent degradation rescue, cell proliferation assays Communications biology Medium 34764413
2020 KPNB1 (Karyopherin β1) is required for nuclear import of CRBN; CRBN nuclear localization is necessary for pomalidomide-dependent degradation of the nuclear transcription factor Aiolos, whereas the cytoplasmic translation factor GSPT1 is degraded by CC-885 only when CRBN is present in the cytoplasm, demonstrating that subcellular distribution of CRBN is critical for drug efficacy. Genome-wide shRNA screen, genetic knockdown of KPNB1, subcellular fractionation, nuclear import assays, substrate degradation assays Scientific reports Medium 32132601
2014 CRBN negatively regulates AMPK activity in vivo and in vitro, and thereby activates mTOR-dependent protein synthesis; CRBN-deficient mice show repressed protein translation via the AMPK-mTOR cascade. A pathogenic C-terminal 24-amino acid deletion mutant (found in human patients with mild mental retardation) fails to rescue mTOR-dependent translational repression in CRBN-deficient fibroblasts. CRBN knockout mice, ectopic expression of wild-type vs. mutant CRBN, AMPK activity assays, mTOR signaling readouts, protein synthesis measurements The Journal of biological chemistry Medium 24993823
2021 CRBN inhibits TRAF6-induced ubiquitination of ECSIT (blocking mitochondrial ROS production needed for bactericidal activity) and ubiquitination of BECN1 (Beclin 1), thereby suppressing autophagy; CRBN mitochondrial localization is increased upon TLR4 stimulation, and CRBN knockdown/knockout enhances autophagy and bactericidal activity against S. typhimurium. Co-immunoprecipitation, ubiquitination assays, CRBN knockdown/knockout cell models, mitochondrial localization by fractionation, mROS measurement, bacterial infection assays Frontiers in immunology Medium 31620128
2021 Thalidomide does not affect AMPK activation or CRBN-AMPK α subunit binding affinity, indicating that CRBN's negative regulation of AMPK operates through a mechanism independent of the IMiD-binding region. The N-terminal region and C-terminal tail of CRBN (distinct from the IMiD binding site) are required for interaction with the AMPK α subunit. AMPK activity assays with/without thalidomide, binding affinity measurements, domain-deletion/mutagenesis analysis of CRBN Pharmaceuticals Medium 34073624
2020 The CUL4-DDB1-CRBN E3 ubiquitin ligase promotes polyubiquitination and proteasomal degradation of ClC-2 chloride channels; CRBN co-exists in the same complex with ClC-2 and promotes its degradation. The CRBN-targeting drug lenalidomide promotes ClC-2 degradation, while the cullin inhibitor MLN4924 attenuates it. Disease-associated ClC-2 mutants causing aldosteronism or leukodystrophy show opposite alterations in CUL4-mediated proteostasis. Co-immunoprecipitation, ubiquitination assays, pharmacological modulation (lenalidomide, MLN4924), heterologous expression and native cell studies, functional electrophysiology Cells Medium 32466489
2025 PCMT1 (protein carboxymethyltransferase) promotes formation of C-terminal cyclic imide modifications on C-terminal asparagine residues of CRBN substrates (including glutamine synthetase/GLUL and inorganic pyrophosphatase 1/PPA1), thereby generating the degron recognized by CRBN. PCMT1 and CRBN co-regulate the levels of these metabolic enzymes in vitro, in cells, and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mice. In vitro enzymatic assays, cell-based protein stability experiments, in vivo mouse models (CRBN KO), chemical biology tools, co-regulation analysis Nature chemical biology High 41461925
2025 PCMT1 promotes formation of the C-terminal cyclic imide degron on CRBN substrates glutamine synthetase (GLUL) and PPA1 (preprint version of the same discovery); PCMT1 and CRBN co-regulate these metabolic enzymes in vitro, in cells, and in vivo. In vitro enzymatic assays, cell-based protein stability assays, mouse models bioRxivpreprint Medium 40196534
2020 Thalidomide-induced degradation of SALL4 via CRBN is responsible for disruption of human iPSC mesendoderm/lateral plate mesoderm differentiation; CRBN V388I mutation or SALL4 G416A mutation abrogates both SALL4 degradation and the teratogenic effects on LPM differentiation, establishing a CRBN-SALL4 axis in thalidomide teratogenicity. Engineered hiPSC lines with CRBN or SALL4 point mutations, differentiation assays, SALL4 protein stability assays Scientific reports High 32071327
2020 CC-885 (a cereblon modulator) selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and proteasomal degradation in non-small cell lung cancer cells, identifying PLK1 as a neosubstrate of CUL4-CRBN induced by CC-885. Ubiquitination assays, CRBN and p97 genetic depletion (rescue experiments), protein degradation assays, in vitro and in vivo tumor models Molecular therapy oncolytics Medium 32728610
2021 CC-885 selectively induces CRBN-dependent ubiquitination and proteasomal degradation of CDK4 in multiple myeloma cells; CDK4 destruction by CC-885 decreases RB phosphorylation and suppresses E2F downstream gene expression. Ubiquitination assays, CRBN genetic ablation (rescue), protein degradation assays, RB phosphorylation readouts, cell cycle analysis Biochemical and biophysical research communications Medium 33676183
2025 A molecular glue degrader (MRT-31619) drives homo-dimerization of CRBN via two molecules assembling into a helix-like structure that mimics a neosubstrate G-loop degron, promoting CRBN self-ubiquitination and fast, potent, selective degradation by the ubiquitin-proteasome system. Cryo-EM structure of the CRBN homodimer reveals this unique mechanism. Cryo-EM structure determination, cellular degradation assays, quantitative proteomics, chemical biology Nature communications High 41258141
2023 CRBN interacts with and mediates AZD7762-dependent ubiquitination of BAG3; AZD7762-induced BAG3 degradation is CRBN-dependent and occurs through the ubiquitin-proteasome pathway, independent of Chk1 expression or activity. Co-immunoprecipitation, ubiquitination assays, CRBN-dependent rescue experiments, western blot, cell viability assays Anti-cancer drugs Low 37449977
2025 MORF4L1 (a chromatin-remodeling MRG family protein) is identified as an endogenous CRBN substrate; CRBN promotes MORF4L1 ubiquitination and degradation under physiological conditions, further enhanced by CC-885, as shown by Co-IP and structural modeling. Proteomic analysis, co-immunoprecipitation, structural modeling, protein stability assays Scientific reports Low 39827217
2025 USP2 directly interacts with CRBN and promotes its deubiquitination and stabilization in senescent liver cancer cells, making them sensitive to CRBN-based PROTAC therapy. Co-immunoprecipitation, deubiquitination assays, genetic USP2 depletion, protein stability measurements Gastroenterology Low 38262581
2019 Crystal structures of hydrolyzed thalidomide metabolites bound to the CRBN thalidomide-binding domain reveal binding mode of minimalistic CRBN effectors; a de-novo CRBN effector was designed from this scaffold that degrades the neosubstrate IKZF3 in cells. X-ray crystallography of CRBN-ligand complexes, cell-based IKZF3 degradation assays Journal of medicinal chemistry Medium 31251063
2025 A crystal structure of the DDB1/CRBN/lenalidomide complex with greater resolution than previously published was generated; dynamic modeling using this structure helped explain the differential impact of CRBN missense mutations on IMiD and CELMoD agent activity, including identification of mutations that can be overcome by more potent CELMoDs. X-ray crystallography (DDB1-CRBN-lenalidomide complex), structure-guided dynamic modeling, functional cell-based degradation assays, confirmatory mutagenesis experiments Blood High 39841463

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 870 25043012
2013 Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). British journal of haematology 524 24328678
2016 Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature 481 26909574
2018 Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science (New York, N.Y.) 405 30385546
2016 Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 224 27458004
2000 MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 223 10646593
2015 Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood cancer journal 189 26430725
2020 Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma. Journal of medicinal chemistry 167 32130004
2017 pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase. Nature communications 145 28530236
2021 Developments of CRBN-based PROTACs as potential therapeutic agents. European journal of medicinal chemistry 120 34411892
2022 Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders. Chemical Society reviews 110 35796627
2013 High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. British journal of haematology 110 23565715
2018 Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 109 30042095
2018 Crbn I391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice. Blood 101 30064974
2021 Effective degradation of EGFRL858R+T790M mutant proteins by CRBN-based PROTACs through both proteosome and autophagy/lysosome degradation systems. European journal of medicinal chemistry 97 33773286
2022 Novel CRBN-Recruiting Proteolysis-Targeting Chimeras as Degraders of Stimulator of Interferon Genes with In Vivo Anti-Inflammatory Efficacy. Journal of medicinal chemistry 87 35452223
2014 CRL4A(CRBN) E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis. Nature communications 87 24845235
2020 ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells. Nature chemical biology 75 32958952
2017 p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates. Proceedings of the National Academy of Sciences of the United States of America 73 28320958
2006 FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions. American journal of medical genetics. Part A 59 17036314
2017 Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1. Journal of medicinal chemistry 57 28358507
2021 The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma. Molecular cell 52 33571422
2021 Circ_0114428 Regulates Sepsis-Induced Kidney Injury by Targeting the miR-495-3p/CRBN Axis. Inflammation 46 33830389
2021 USP15 antagonizes CRL4CRBN-mediated ubiquitylation of glutamine synthetase and neosubstrates. Proceedings of the National Academy of Sciences of the United States of America 43 34583995
2024 Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs. Gastroenterology 42 38262581
2019 De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives. Journal of medicinal chemistry 41 31251063
2007 Primary function analysis of human mental retardation related gene CRBN. Molecular biology reports 40 17380424
2020 Induction of SIRT1 by melatonin improves alcohol-mediated oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway. Journal of pineal research 37 32053237
2024 Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library. Journal of the American Chemical Society 31 39499896
2020 A Cereblon Modulator CC-885 Induces CRBN- and p97-Dependent PLK1 Degradation and Synergizes with Volasertib to Suppress Lung Cancer. Molecular therapy oncolytics 31 32728610
2022 Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo. European journal of medicinal chemistry 29 35691176
2020 Thalidomide Inhibits Human iPSC Mesendoderm Differentiation by Modulating CRBN-dependent Degradation of SALL4. Scientific reports 29 32071327
2020 Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide. Scientific reports 29 32132601
2014 Functional effects of a pathogenic mutation in Cereblon (CRBN) on the regulation of protein synthesis via the AMPK-mTOR cascade. The Journal of biological chemistry 27 24993823
2023 Design, synthesis and biological evaluation of the tumor hypoxia-activated PROTACs bearing caged CRBN E3 ligase ligands. Bioorganic & medicinal chemistry 26 36906965
2018 Expression of CRBN, IKZF1, and IKZF3 does not predict lenalidomide sensitivity and mutations in the cereblon pathway are infrequent in multiple myeloma. Leukemia & lymphoma 26 29718735
2017 A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family. Journal of medical genetics 26 28143899
2018 IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation. Blood advances 25 29496670
2022 Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorganic & medicinal chemistry letters 24 35231578
2022 CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma. Cancers 24 36139651
2021 Cereblon modulator CC-885 induces CRBN-dependent ubiquitination and degradation of CDK4 in multiple myeloma. Biochemical and biophysical research communications 24 33676183
2021 Selective degradation-inducing probes for studying cereblon (CRBN) biology. RSC medicinal chemistry 24 34458741
2019 CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1. Frontiers in immunology 24 31620128
2019 CRBN knockdown mitigates lipopolysaccharide-induced acute lung injury by suppression of oxidative stress and endoplasmic reticulum (ER) stress associated NF-κB signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 31865141
2023 Discovery of highly efficient CRBN-recruiting HPK1-PROTAC as a potential chemical tool for investigation of scaffolding roles in TCR signaling. Bioorganic chemistry 21 38086239
2022 Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): Investigation of their binding mode and antiproliferative effects against myeloma cell lines. European journal of medicinal chemistry 21 36476642
2004 Candidate genes for recessive non-syndromic mental retardation on chromosome 3p (MRT2A). Clinical genetics 20 15151510
2023 A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity. Chembiochem : a European journal of chemical biology 19 37418539
2020 CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy. Cells 19 32466489
2021 General Stepwise Approach to Optimize a TR-FRET Assay for Characterizing the BRD/PROTAC/CRBN Ternary Complex. ACS pharmacology & translational science 18 33860212
2021 Design, Synthesis, and Biological Evaluation of HDAC Degraders with CRBN E3 Ligase Ligands. Molecules (Basel, Switzerland) 18 34885822
2024 Crbn-based molecular Glues: Breakthroughs and perspectives. Bioorganic & medicinal chemistry 17 38552596
2024 SuFEx-based chemical diversification for the systematic discovery of CRBN molecular glues. Bioorganic & medicinal chemistry 16 38608634
2024 CRBN-PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications. Chemical biology & drug design 16 39496477
2018 Cereblon (CRBN) deletion reverses streptozotocin induced diabetic osteoporosis in mice. Biochemical and biophysical research communications 14 29353038
2021 PLZF and its fusion proteins are pomalidomide-dependent CRBN neosubstrates. Communications biology 12 34764413
2025 Discovery of a Novel CRBN-Recruiting cGAS PROTAC Degrader for the Treatment of Ulcerative Colitis. Journal of medicinal chemistry 11 40012371
2021 Ablation of CRBN induces loss of type I collagen and SCH in mouse skin by fibroblast senescence via the p38 MAPK pathway. Aging 11 33658395
2016 Genomic and in silico analyses of CRBN gene and thalidomide embryopathy in humans. Reproductive toxicology (Elmsford, N.Y.) 10 27751757
2025 Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation. ACS chemical biology 9 39753207
2023 Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway. Experimental & molecular medicine 9 37488285
2022 Discovery of pan-IAP degraders via a CRBN recruiting mechanism. European journal of medicinal chemistry 9 36410083
2015 Microduplications of 3p26.3p26.2 containing CRBN gene in patients with intellectual disability and behavior abnormalities. European journal of medical genetics 9 25858704
2023 Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN. Cells 8 36766811
2021 The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients. Journal of clinical medicine 8 34207079
2019 Polymorphisms in the promotor region of the CRBN gene as a predictive factor for peripheral neuropathy in the course of thalidomide-based chemotherapy in multiple myeloma patients. British journal of haematology 8 31115923
2025 A method to identify small molecule/protein pairs susceptible to protein ubiquitination by the CRBN E3 ligase. Chemical science 7 40191122
2021 Regulation of AMPK Activity by CRBN Is Independent of the Thalidomide-CRL4CRBN Protein Degradation Axis. Pharmaceuticals (Basel, Switzerland) 7 34073624
2018 Polymorphisms in the promoter region of the CRBN gene as a predictive factor for the first-line CTD therapy in multiple myeloma patients. Oncotarget 7 29844872
2025 PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates. Nature chemical biology 6 41461925
2023 Transfection of clMagR/clCry4 imparts MR-T2 imaging contrast properties to living organisms (E. coli) in the presence of Fe3+ by endogenous formation of iron oxide nanoparticles. Frontiers in molecular biosciences 6 36876047
2023 High levels of CRBN isoform lacking IMiDs binding domain predicts for a worse response to IMiDs-based upfront therapy in newly diagnosed myeloma patients. Clinical and experimental medicine 6 37815734
2025 Identification of MORF4L1 as an endogenous substrate of CRBN and its potential role as a therapeutic target in cancer. Scientific reports 5 39827217
2025 Evaluating the impact of CRBN mutations on response to immunomodulatory drugs and novel cereblon E3 ligase modulators in myeloma. Blood 5 39841463
2025 PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates. bioRxiv : the preprint server for biology 5 40196534
2023 Discovery of Highly Potent CRBN Ligands and Insight into Their Binding Mode through Molecular Docking and Molecular Dynamics Simulations. ChemMedChem 5 36750890
2022 Discovery of novel potential CRBN modulators through structure-based virtual screening and bioassay. Journal of molecular graphics & modelling 5 36088765
2020 Generation of a lenalidomide-sensitive syngeneic murine in vivo multiple myeloma model by expression of CrbnI391V. Experimental hematology 5 33186626
2025 Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider. Regulatory toxicology and pharmacology : RTP 4 40015443
2025 Discovery of a novel molecular glue degrader targeting GSPT1/2 with a non-IMiD-based CRBN binder. European journal of medicinal chemistry 4 40252382
2025 Discovery of TQ-3959 as a Potent and Orally Bioavailable BTK PROTAC Degrader Incorporating a Novel Benzisoxazole-Based CRBN Ligand for the Treatment of B-Cell Malignancies. Journal of medicinal chemistry 4 40731261
2022 Design, synthesis and biological evaluation of novel quinazolinone derivatives as CRBN E3 ligase modulators. European journal of medicinal chemistry 4 36577219
2021 Combined scaffold hopping, molecular screening with dynamic simulation to screen potent CRBN ligands. Journal of cellular biochemistry 4 33938033
2021 Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy. Frontiers in genetics 4 34249098
2025 CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer. Life sciences 3 39914588
2025 In-cell proximity target validation methods for heterobifunctional molecules with CRBN- or VHL-binder using AirID. Communications biology 3 40885760
2025 Discovery of CRBN-recruiting PROTAC degraders of the METTL3-METTL14 complex. Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 3 41245600
2023 AZD7762 induces CRBN dependent BAG3 degradation through ubiquitin-proteasome pathway. Anti-cancer drugs 3 37449977
2018 [Molecular Mechanism of CRBN in the Activity of Lenalidomid eagainst Myeloma--Review]. Zhongguo shi yan xue ye xue za zhi 3 30111438
2016 An Acetyldegron Triggers CRBN to Take Down the "Q". Molecular cell 3 26990985
2025 Targeted degradation of GOLM1 by CC-885 via CRL4-CRBN E3 ligase inhibits hepatocellular carcinoma progression. Cellular signalling 2 39986359
2025 Discovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader. RSC medicinal chemistry 2 40510905
2025 Beyond the G-Loop: CRBN Molecular Glues Potently Target VAV1 via a Novel SH3 RT-Loop Degron. bioRxiv : the preprint server for biology 2 40661494
2025 Design, synthesis, and biological evaluation of novel PROTACs based on unnatural dipeptide CRBN ligands. European journal of medicinal chemistry 2 41313965
2025 Lung-specific CRBN knockout attenuates influenza a virus-induced acute lung injury in mice: a potential therapeutic approach. BMC infectious diseases 1 39833740
2025 Discovery of potent CRBN-recruiting epidermal growth factor receptor (EGFR) degraders in vitro. Investigational new drugs 1 40301162
2025 GCK inhibition enhances iberdomide antimyeloma effects by promoting IKZF1 degradation via a CRBN-independent mechanism. Blood neoplasia 1 40792016
2025 Synthesis and Structure-Activity Relationships of CRBN-Recruiting ZBTB11 Molecular Glue Degraders. Journal of medicinal chemistry 1 40911408
2025 A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation. Nature communications 1 41258141
2025 Discovery of a dual-target CRBN-mediated degrader for IKZF1/3 and GSPT1 proteins. Bioorganic chemistry 1 41411691

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