cereblon

Target id: 3086

Nomenclature: cereblon

Family: E3 ubiquitin ligase components

Gene and Protein Information
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
mental retardation, non-syndromic, autosomal recessive, 2A \| MRT2A

Previous and Unofficial Names

mental retardation, non-syndromic, autosomal recessive, 2A | MRT2A

Database Links
Alphafold	Q96SW2 (Hs), Q8C7D2 (Mm), Q56AP7 (Rn)
ChEMBL Target	CHEMBL3763008 (Hs)
Ensembl Gene	ENSG00000113851 (Hs), ENSMUSG00000005362 (Mm), ENSRNOG00000006534 (Rn)
Entrez Gene	51185 (Hs), 58799 (Mm), 297498 (Rn)
Human Protein Atlas	ENSG00000113851 (Hs)
KEGG Gene	hsa:51185 (Hs), mmu:58799 (Mm), rno:297498 (Rn)
OMIM	609262 (Hs)
Pharos	Q96SW2 (Hs)
RefSeq Nucleotide	NM_016302 (Hs), NM_175357 (Mm), NM_001015003 (Rn)
RefSeq Protein	NP_057386 (Hs), NP_780566 (Mm), NP_001015003 (Rn)
UniProtKB	Q96SW2 (Hs), Q8C7D2 (Mm), Q56AP7 (Rn)
Wikipedia	CRBN (Hs)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	Ternary complex structure of Cereblon-DDB1 bound to IKZF2(ZF2) and the molecular glue DKY709
PDB Id:	7U8F
Ligand:	NVP-DKY709
Resolution:	3.15Å
Species:	Human
References:	3

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Inhibitors

Key to terms and symbols

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Ligand											Sp.	Action	Value	Parameter	Reference
SJ995973											Hs	Binding	7.8	pIC₅₀	24
⤷	pIC₅₀ 7.8 (IC₅₀ 1.7x10^-8 M) [24]

Other Binding Ligands

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
thalidomide		Hs	Binding	8.1	pK_d	17
⤷	pK_d 8.1 (K_d 8.5x10^-9 M) [17] Description: Determined in a BiaCore assay using immobilised thalidomide and recombinant cereblon protein.
MS40		Hs	Binding	4.8	pK_d	20
⤷	pK_d 4.8 (K_d 1.48x10^-5 M) [20] Description: Binding affinity for CRBN’s C-terminal thalidomide binding domain
AK-2292		Hs	Binding	9.8	pK_i	19
⤷	pK_i 9.8 (K_i 1.7x10^-10 M) [19]
compound 7f [PMID: 31251063]		N/A	Binding	7.7	pK_i	12-13
⤷	pK_i 7.7 (K_i 2x10^-8 M) [12-13] Description: K_i determined using the single-domain bacterial CRBN homologue from Magnetospirillum gryphiswaldense (MsCI4) in a FRET assay.
TX-16		Hs	Binding	5.8	pK_i	29
⤷	pK_i 5.8 (K_i 1.4x10^-6 M) [29]
MG-277		Hs	Binding	8.5	pIC₅₀	30
⤷	pIC₅₀ 8.5 (IC₅₀ 3.1x10^-9 M) [30] 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		Hs	Binding	<8.0	pIC₅₀	30
⤷	pIC₅₀ <8.0 (IC₅₀ >1x10^-8 M) [30]
TL12-186		Hs	Binding	7.9	pIC₅₀	16
⤷	pIC₅₀ 7.9 (IC₅₀ 1.2x10^-8 M) [16] Description: Half-maximal inhibitory concentration determined using an AlphaScreen engagement assay, measuring displacement of biotinylated thalidomide from CRBN
mezigdomide		Hs	Binding	7.5	pIC₅₀	11
⤷	pIC₅₀ 7.5 (IC₅₀ 3x10^-8 M) [11]
dBRD9		Hs	Binding	7.5	pIC₅₀	27
⤷	pIC₅₀ 7.5 (IC₅₀ 3.13x10^-8 M) [27] Description: AlphaScreen competitive ligand binding assay using the CRBN-DDB1 complex.
avadomide		Hs	Binding	7.3	pIC₅₀	8,10
⤷	pIC₅₀ 7.3 (IC₅₀ 5.4x10^-8 M) [8,10] Description: Inhibition of LPS-induced IL-1β production by human peripheral blood mononuclear cells.
iberdomide		Hs	Binding	7.2	pIC₅₀	23
⤷	pIC₅₀ 7.2 (IC₅₀ 6x10^-8 M) [23] Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by CC-220.
dTAG-13		Hs	Binding	7.2	pIC₅₀	25
⤷	pIC₅₀ 7.2 (IC₅₀ 6.42x10^-8 M) [25]
PTD10		Hs	Binding	7.0	pIC₅₀	21
⤷	pIC₅₀ 7.0 (IC₅₀ 1.07x10^-7 M) [21] Description: Measuring target engagement in a NanoBRET competitive displacement assay.
NVP-DKY709		Hs	Binding	6.9	pIC₅₀	3
⤷	pIC₅₀ 6.9 (IC₅₀ 1.3x10^-7 M) [3] Description: CRBN binding
pomalidomide		Hs	Binding	5.9	pIC₅₀	23
⤷	pIC₅₀ 5.9 (IC₅₀ 1.2x10^-6 M) [23] Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by pomalidomide.
lenalidomide		Hs	Binding	5.8	pIC₅₀	23
⤷	pIC₅₀ 5.8 (IC₅₀ 1.5x10^-6 M) [23] Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by lenalidomide.
CBPD-268		Hs	Binding	5.7	pIC₅₀	5
⤷	pIC₅₀ 5.7 (IC₅₀ 1.8x10^-6 M) [5]
golcadomide		Hs	Binding	-	-	1
⤷	[1]

Immunopharmacology Comments
Cereblon is a direct molecular target for the immunomodulatory and antiproliferative activities of thalidomide and its analogues (e.g lenalidomide and pomalidomide) [2,4,17,22]. 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 [9,18].

Immunopharmacology Comments

Cereblon is a direct molecular target for the immunomodulatory and antiproliferative activities of thalidomide and its analogues (e.g lenalidomide and pomalidomide) [2,4,17,22]. 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 [9,18].

Immuno Process Associations

Immuno Process:

Cellular signalling

Biologically Significant Variant Comments
Loss-of-function mutations in cereblon have been identified in patients with autosomal recessive nonsyndromal mental retardation [14-15,28].

Biologically Significant Variant Comments

Loss-of-function mutations in cereblon have been identified in patients with autosomal recessive nonsyndromal mental retardation [14-15,28].

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 CRL4^CRBN. Under normal conditions CRL4^CRBN recognises endogenous substrates including glutamine synthetase [26], MEIS2 [7], and amyloid precursor protein [6]. Exogenous drugs that bind to cereblon are able to allosterically modify CRL4^CRBN 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 [17]. The derivatives lenalidomide and pomalidomide also bind (human) cereblon [4]. 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 (K_Ca1.1; KCNMA1) in regions of the brain that are associated with memory and learning [14-15]. 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.

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 CRL4^CRBN. Under normal conditions CRL4^CRBN recognises endogenous substrates including glutamine synthetase [26], MEIS2 [7], and amyloid precursor protein [6]. Exogenous drugs that bind to cereblon are able to allosterically modify CRL4^CRBN 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 [17]. The derivatives lenalidomide and pomalidomide also bind (human) cereblon [4]. 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 (K_Ca1.1; KCNMA1) in regions of the brain that are associated with memory and learning [14-15].

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. Anton MSC, Buchholz TJ, Lopez-Girona A, Narla RK, Pourdehnad M. (2022) Methods of treating non-hodgkin lymphoma using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione. Patent number: US20220324855A1. Assignee: Celgene Corporation. Priority date: 24/06/2022. Publication date: 13/10/2022.

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

3. Bonazzi S, d'Hennezel E, Beckwith REJ, Xu L, Fazal A, Magracheva A, Ramesh R, Cernijenko A, Antonakos B, Bhang HC et al.. (2023) Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy. Cell Chem Biol, 30 (3): 235-247.e12. [PMID:36863346]

4. 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]

5. Chen Z, Wang M, Wu D, Bai L, Xu T, Metwally H, Wang Y, McEachern D, Zhao L, Li R et al.. (2024) Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression. J Med Chem, [Epub ahead of print]. [PMID:38477974]

6. 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]

7. 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]

8. 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.

9. 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]

10. 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]

11. Hansen JD, Correa M, Nagy MA, Alexander M, Plantevin V, Grant V, Whitefield B, Huang D, Kercher T, Harris R et al.. (2020) Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma. J Med Chem, 63 (13): 6648-6676. [PMID:32130004]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. Kaneshige A, Bai L, Wang M, McEachern D, Meagher JL, Xu R, Kirchhoff PD, Wen B, Sun D, Stuckey JA et al.. (2023) Discovery of a Potent and Selective STAT5 PROTAC Degrader with Strong Antitumor Activity In Vivo in Acute Myeloid Leukemia. J Med Chem, 66 (4): 2717-2743. [PMID:36735833]

20. 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, 41 (24): 3328-3340. [PMID:35525905]

21. Li YQ, Lannigan WG, Davoodi S, Daryaee F, Corrionero A, Alfonso P, Rodriguez-Santamaria JA, Wang N, Haley JD, Tonge PJ. (2023) Discovery of Novel Bruton’s Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy. Journal of Mediconal Chemistry,. DOI: 10.1021/acs.jmedchem.3c00176

22. 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]

23. 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]

24. Min J, Mayasundari A, Keramatnia F, Jonchere B, Yang SW, Jarusiewicz J, Actis M, Das S, Young B, Slavish J et al.. (2021) Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs. Angew Chem Int Ed Engl, 60 (51): 26663-26670. [PMID:34614283]

25. 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]

26. 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]

27. 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]

28. 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]

29. Xiang W, Zhao L, Han X, Xu T, Kregel S, Wang M, Miao B, Qin C, Wang M, McEachern D et al.. (2023) Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR + Human Prostate Cancer. J Med Chem, 66 (18): 13280-13303. [PMID:37683104]

30. 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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