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cereblon

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 3086

Nomenclature: cereblon

Family: E3 ubiquitin ligase components

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 442 3p26.2 CRBN cereblon
Mouse - 445 6 E1 Crbn cereblon
Rat - 445 4q41 Crbn cereblon
Gene and Protein Information Comments
Transcript variants encoding different protein isoforms have been identified for the human and mouse CRBN genes.
Previous and Unofficial Names Click here for help
mental retardation, non-syndromic, autosomal recessive, 2A | MRT2A
Database Links Click here for help
Alphafold
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SJ995973 Small molecule or natural product Hs Binding 7.8 pIC50 20
pIC50 7.8 (IC50 1.7x10-8 M) [20]
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
thalidomide Small molecule or natural product Approved drug Immunopharmacology Ligand Hs Binding 8.1 pKd 13
pKd 8.1 (Kd 8.5x10-9 M) [13]
Description: Determined in a BiaCore assay using immobilised thalidomide and recombinant cereblon protein.
MS40 Small molecule or natural product Click here for species-specific activity table Hs Binding 4.8 pKd 15
pKd 4.8 (Kd 1.48x10-5 M) [15]
Description: Binding affinity for CRBN’s C-terminal thalidomide binding domain
compound 7f [PMID: 31251063] Small molecule or natural product Primary target of this compound N/A Binding 7.7 pKi 8-9
pKi 7.7 (Ki 2x10-8 M) [8-9]
Description: Ki determined using the single-domain bacterial CRBN homologue from Magnetospirillum gryphiswaldense (MsCI4) in a FRET assay.
MG-277 Small molecule or natural product Hs Binding 8.5 pIC50 23
pIC50 8.5 (IC50 3.1x10-9 M) [23]
Description: Binding affinity to cereblon in human RV4:11/IRMI-2 cells that express p53 mutation Y236H/R249G assessed as cell growth inhibition measured after 4 days.
MD-222 Small molecule or natural product Hs Binding <8.0 pIC50 23
pIC50 <8.0 (IC50 >1x10-8 M) [23]
TL12-186 Small molecule or natural product Hs Binding 7.9 pIC50 12
pIC50 7.9 (IC50 1.2x10-8 M) [12]
Description: Half-maximal inhibitory concentration determined using an AlphaScreen engagement assay, measuring displacement of biotinylated thalidomide from CRBN
dBRD9 Small molecule or natural product Click here for species-specific activity table Hs Binding 7.5 pIC50 21
pIC50 7.5 (IC50 3.13x10-8 M) [21]
Description: AlphaScreen competitive ligand binding assay using the CRBN-DDB1 complex.
avadomide Small molecule or natural product Immunopharmacology Ligand Hs Binding 7.3 pIC50 5,7
pIC50 7.3 (IC50 5.4x10-8 M) [5,7]
Description: Inhibition of LPS-induced IL-1β production by human peripheral blood mononuclear cells.
iberdomide Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Binding 7.2 pIC50 17
pIC50 7.2 (IC50 6x10-8 M) [17]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by CC-220.
dTAG-13 Small molecule or natural product Hs Binding 7.2 pIC50 18
pIC50 7.2 (IC50 6.42x10-8 M) [18]
pomalidomide Small molecule or natural product Approved drug Immunopharmacology Ligand Hs Binding 5.9 pIC50 17
pIC50 5.9 (IC50 1.2x10-6 M) [17]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by pomalidomide.
lenalidomide Small molecule or natural product Approved drug Immunopharmacology Ligand Hs Binding 5.8 pIC50 17
pIC50 5.8 (IC50 1.5x10-6 M) [17]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by lenalidomide.
Immunopharmacology Comments
Cereblon is a direct molecular target for the immunomodulatory and antiproliferative activities of thalidomide and its analogues (e.g lenalidomide and pomalidomide) [1-2,13,16]. Mechanistically, this class of drugs has been shown to enhance recruitment of the Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors (Ikaros and Aiolos are transcriptional repressors of IL-2 expression) to the cereblon/CUL4 E3 ubiquitin ligase complex, which increases proteasomal degradation of Ikaros and Aiolos and elevates IL-2 expression and activation of T cells, to bring about their immunomodulatory and antiproliferative effects [6,14].
Immuno Process Associations
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0016567 protein ubiquitination IMP
Biologically Significant Variant Comments
Loss-of-function mutations in cereblon have been identified in patients with autosomal recessive nonsyndromal mental retardation [10-11,22].
General Comments
Cereblon is a substrate adaptor module of E3 ubiquitin ligase. It has no inherent enzymatic activity, but rather controls the substrate specificity of E3-mediated protein ubiquitin modifications. Cereblon forms an E3 complex with damaged DNA binding protein 1 (DDB1), Cullin 4 (CUL4) and regulator of cullins 1 (ROC1), abbreviated here as CRL4CRBN. Under normal conditions CRL4CRBN recognises endogenous substrates including glutamine synthetase [19], MEIS2 [4], and amyloid precursor protein [3]. Exogenous drugs that bind to cereblon are able to allosterically modify CRL4CRBN substrate specificity. In particular the immunomodulatory thalidomide family drugs are know to alter E3 substrate selectivity. Binding of thalidomide to cereblon mediates this drug's teratogenicity, via disruption of fibroblast growth factor 8 expression and limb bud outgrowth [13]. The derivatives lenalidomide and pomalidomide also bind (human) cereblon [2]. All of these drugs contain a glutarimide moiety that is accommodated in a hydrophobic binding pocket on the surface of the C-terminal domain of cereblon. Thalidomide type drugs are not teratogenic in mouse or rat .

Evidence points to a role for cereblon in the assembly and neuronal surface expression of large-conductance Ca2+-activated potassium channels (KCa1.1; KCNMA1) in regions of the brain that are associated with memory and learning [10-11].

Note: Cereblon is included in the Enzymes section of the Guide To PHARMACOLOGY as it is part of the E3 compex. We fully acknowledge that the protein has no intrinsic catalytic activity.

References

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1. Asatsuma-Okumura T, Ito T, Handa H. (2019) Molecular mechanisms of cereblon-based drugs. Pharmacol Ther, 202: 132-139. [PMID:31202702]

2. Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, Corral LG, Ren YJ, Wang M et al.. (2014) Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol, 21 (9): 803-9. [PMID:25108355]

3. Del Prete D, Rice RC, Rajadhyaksha AM, D'Adamio L. (2016) Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration. J Biol Chem, 291 (33): 17209-27. [PMID:27325702]

4. Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM et al.. (2014) Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature, 512 (7512): 49-53. [PMID:25043012]

5. Gandhi A, Dimartino J, Chopra R. (2014) Methods for the treatment of locally advanced breast cancer. Patent number: WO2014039960A1. Assignee: Celgene Corporation. Priority date: 10/09/2012. Publication date: 13/03/2014.

6. Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A et al.. (2014) 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.). Br J Haematol, 164 (6): 811-21. [PMID:24328678]

7. Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, Bjorklund C, Havens CG, Lu G, Rychak E et al.. (2015) CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood, 126 (6): 779-89. [PMID:26002965]

8. Hartmann MD, Boichenko I, Coles M, Zanini F, Lupas AN, Hernandez Alvarez B. (2014) Thalidomide mimics uridine binding to an aromatic cage in cereblon. J Struct Biol, 188 (3): 225-32. [PMID:25448889]

9. Heim C, Pliatsika D, Mousavizadeh F, Bär K, Hernandez Alvarez B, Giannis A, Hartmann MD. (2019) De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives. J Med Chem, 62 (14): 6615-6629. [PMID:31251063]

10. Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM. (2008) Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics, 9 (3): 219-23. [PMID:18414909]

11. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP. (2004) A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology, 63 (10): 1927-31. [PMID:15557513]

12. Huang HT, Dobrovolsky D, Paulk J, Yang G, Weisberg EL, Doctor ZM, Buckley DL, Cho JH, Ko E, Jang J et al.. (2018) A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader. Cell Chem Biol, 25 (1): 88-99.e6. [PMID:29129717]

13. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. (2010) Identification of a primary target of thalidomide teratogenicity. Science, 327 (5971): 1345-50. [PMID:20223979]

14. Ito T, Handa H. (2016) Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. Int J Hematol, 104 (3): 293-9. [PMID:27460676]

15. Li D, Yu X, Kottur J, Gong W, Zhang Z, Storey AJ, Tsai YH, Uryu H, Shen Y, Byrum SD et al.. (2022) Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic. Oncogene, [Epub ahead of print]. DOI: 10.1038/s41388-022-02340-8 [PMID:35525905]

16. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M et al.. (2012) Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia, 26 (11): 2326-35. [PMID:22552008]

17. Matyskiela ME, Zhang W, Man HW, Muller G, Khambatta G, Baculi F, Hickman M, LeBrun L, Pagarigan B, Carmel G et al.. (2018) A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. J Med Chem, 61 (2): 535-542. [PMID:28425720]

18. Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S, Yang A, Leggett AL, Erb MA, Lawlor MA, Souza A et al.. (2018) The dTAG system for immediate and target-specific protein degradation. Nat Chem Biol, 14 (5): 431-441. [PMID:29581585]

19. Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ, Harrison JS, Yim JH, Lee SG, Handa H, Kuhlman B et al.. (2016) Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon. Mol Cell, 61 (6): 809-20. [PMID:26990986]

20. Rankovic Z, Min J, Mayasundari A, Keramatnia F, Jonchere B, Yang SW, Jarusiewicz JA, Actis M, Das S, Young BM et al.. (2021) Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs. Angew Chem Int Ed Engl, [Epub ahead of print]. DOI: 10.1002/anie.202108848 [PMID:34614283]

21. Remillard D, Buckley DL, Paulk J, Brien GL, Sonnett M, Seo HS, Dastjerdi S, Wühr M, Dhe-Paganon S, Armstrong SA et al.. (2017) Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands. Angew Chem Int Ed Engl, 56 (21): 5738-5743. [PMID:28418626]

22. Sheereen A, Alaamery M, Bawazeer S, Al Yafee Y, Massadeh S, Eyaid W. (2017) A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family. J Med Genet, 54 (4): 236-240. [PMID:28143899]

23. Yang J, Li Y, Aguilar A, Liu Z, Yang CY, Wang S. (2019) Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders. J Med Chem, 62 (21): 9471-9487. [PMID:31560543]

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