Target Information
| Target General Information | Top | |||||
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| Target ID |
T27861
(Former ID: TTDI01546)
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| Target Name |
Protein cereblon (CRBN)
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| Synonyms |
Protein cereblon
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| Gene Name |
CRBN
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 9 Target-related Diseases | + | ||||
| 1 | Lupus erythematosus [ICD-11: 4A40] | |||||
| 2 | Sarcoidosis [ICD-11: 4B20] | |||||
| 3 | Brain cancer [ICD-11: 2A00] | |||||
| 4 | Diffuse large B-cell lymphoma [ICD-11: 2A81] | |||||
| 5 | Liver cancer [ICD-11: 2C12] | |||||
| 6 | Lymphoma [ICD-11: 2A80-2A86] | |||||
| 7 | Mature B-cell leukaemia [ICD-11: 2A82] | |||||
| 8 | Multiple myeloma [ICD-11: 2A83] | |||||
| 9 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. May play a role in memory and learning by regulating the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1. Binding of pomalidomide and other thalidomide-related drugs changes the substrate specificity of the human protein, leading to decreased degradation of MEIS2 and other target proteins and increased degradation of MYC, IRF4, IKZF1 and IKZF3.
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| UniProt ID | ||||||
| Sequence |
MAGEGDQQDAAHNMGNHLPLLPAESEEEDEMEVEDQDSKEAKKPNIINFDTSLPTSHTYL
GADMEEFHGRTLHDDDSCQVIPVLPQVMMILIPGQTLPLQLFHPQEVSMVRNLIQKDRTF AVLAYSNVQEREAQFGTTAEIYAYREEQDFGIEIVKVKAIGRQRFKVLELRTQSDGIQQA KVQILPECVLPSTMSAVQLESLNKCQIFPSKPVSREDQCSYKWWQKYQKRKFHCANLTSW PRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPSNPIDFSYRVAACLPIDDVLRIQLLK IGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETL TVYKACNLNLIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTATKKDMSPQKFWGLTRS ALLPTIPDTEDEISPDKVILCL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T60KU1 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | CC-220 | Drug Info | Phase 2 | Sarcoidosis | [2] | |
| 2 | CC-122 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | CC-220 | Drug Info | [4] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | CC-122 | Drug Info | [1], [5] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: CC-220 | Ligand Info | |||||
| Structure Description | Cereblon in complex with DDB1 and CC-220 | PDB:5V3O | ||||
| Method | X-ray diffraction | Resolution | 3.20 Å | Mutation | No | [6] |
| PDB Sequence |
INFDTSLPTS
56 HTYLGADMEE66 FHGRTLHDDD76 SCQVIPVLPQ86 VMMILIPGQT96 LPLQLFHPQE 106 VSMVRNLIQK116 DRTFAVLAYS126 AQFGTTAEIY142 AYREEQDFGI152 EIVKVKAIGR 162 QRFKVLELRT172 QSDGIQQAKV182 QILPECVLPS192 TMSAVQLESL202 NKCQIFPSSY 221 KWWQKYQKRK231 FHCANLTSWP241 RWLYSLYDAE251 TLMDRIKKQL261 REWDDDSLPS 275 NPIDFSYRVA285 ACLPIDDVLR295 IQLLKIGSAI305 QRLRCELDIM315 NKCTSLCCKQ 325 CQETEITTKN335 EIFSLSLCGP345 MAAYVNPHGY355 VHETLTVYKA365 CNLNLIGRPS 375 TEHSWFPGYA385 WTVAQCKICA395 SHIGWKFTAT405 KKDMSPQKFW415 GLTRSALLPT 425 IPD
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Mezigdomide | Ligand Info | |||||
| Structure Description | Cereblon~DDB1 bound to CC-92480 with DDB1 in the linear conformation | PDB:8D7U | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [7] |
| PDB Sequence |
KKPNIINFDT
51 SLPTSHTYLG61 ADMEEFHGRT71 LHDDDSCQVI81 PVLPQVMMIL91 IPGQTLPLQL 101 FHPQEVSMVR111 NLIQKDRTFA121 VLAYSNVQER131 EAQFGTTAEI141 YAYREEQDFG 151 IEIVKVKAIG161 RQRFKVLELR171 TQSDGIQQAK181 VQILPECVLP191 STMSAVQLES 201 LNKCQIFPSK211 PVSREDQCSY221 KWWQKYQKRK231 FHCANLTSWP241 RWLYSLYDAE 251 TLMDRIKKQL261 REWDENLKDD271 SLPSNPIDFS281 YRVAACLPID291 DVLRIQLLKI 301 GSAIQRLRCE311 LDIMNKCTSL321 CCKQCQETEI331 TTKNEIFSLS341 LCGPMAAYVN 351 PHGYVHETLT361 VYKACNLNLI371 GRPSTEHSWF381 PGYAWTVAQC391 KICASHIGWK 401 FTATKKDMSP411 QKFWGLTRSA421 LLPT
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 12 | Degree centrality | 1.29E-03 | Betweenness centrality | 3.95E-04 |
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| Closeness centrality | 2.09E-01 | Radiality | 1.36E+01 | Clustering coefficient | 2.58E-01 |
| Neighborhood connectivity | 1.98E+01 | Topological coefficient | 1.66E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood. 2015 Aug 6;126(6):779-89. | |||||
| REF 2 | ClinicalTrials.gov (NCT02185040) A Pilot Study of CC-220 to Treat Systemic Lupus Erythematosus.. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01421524) Study of CC-122 to Evaluate the Safety, Tolerability, and Effectiveness for Patients With Advanced Solid Tumors, Non-Hodgkin's Lymphoma, or Multiple Myeloma. U.S. National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 6 | A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. J Med Chem. 2018 Jan 25;61(2):535-542. | |||||
| REF 7 | Molecular glue CELMoD compounds are regulators of cereblon conformation. Science. 2022 Nov 4;378(6619):549-553. | |||||
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