Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXH9MDC)

• DOT Name: Protein cereblon (CRBN)
• Gene Name: CRBN
• Related Disease:
  Intellectual disability
  Autosomal recessive non-syndromic intellectual disability
  Intellectual disability, autosomal recessive 2
• UniProt ID: CRBN_HUMAN
• PDB ID: 4M91; 4TZ4; 5FQD; 5HXB; 5V3O; 6BN7; 6BN8; 6BN9; 6BNB; 6BOY; 6H0F; 6H0G; 6UML; 6XK9; 7BQU; 7BQV; 7LPS; 7U8F; 8CVP; 8D7U; 8D7V; 8D7W; 8D7X; 8D7Y; 8D7Z; 8D80; 8D81; 8DEY; 8OIZ; 8OJH
• Pfam ID: PF02190 ; PF03226
• Sequence:
  MAGEGDQQDAAHNMGNHLPLLPAESEEEDEMEVEDQDSKEAKKPNIINFDTSLPTSHTYL
  GADMEEFHGRTLHDDDSCQVIPVLPQVMMILIPGQTLPLQLFHPQEVSMVRNLIQKDRTF
  AVLAYSNVQEREAQFGTTAEIYAYREEQDFGIEIVKVKAIGRQRFKVLELRTQSDGIQQA
  KVQILPECVLPSTMSAVQLESLNKCQIFPSKPVSREDQCSYKWWQKYQKRKFHCANLTSW
  PRWLYSLYDAETLMDRIKKQLREWDENLKDDSLPSNPIDFSYRVAACLPIDDVLRIQLLK
  IGSAIQRLRCELDIMNKCTSLCCKQCQETEITTKNEIFSLSLCGPMAAYVNPHGYVHETL
  TVYKACNLNLIGRPSTEHSWFPGYAWTVAQCKICASHIGWKFTATKKDMSPQKFWGLTRS
  ALLPTIPDTEDEISPDKVILCL
• 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 or ILF2. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. Maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons. Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1. May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism. Plays a negative role in TLR4 signaling by interacting with TRAF6 and ECSIT, leading to inhibition of ECSIT ubiquitination, an important step of the signaling.
• Tissue Specificity: Widely expressed. Highly expressed in brain.
• Reactome Pathway: Potential therapeutics for SARS (R-HSA-9679191)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Moderate	Autosomal recessive	[1]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[2]
Intellectual disability, autosomal recessive 2	DISSN8QX	Limited	Autosomal recessive	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Thalidomide	DM70BU5	Approved	Protein cereblon (CRBN) affects the response to substance of Thalidomide.	[12]
Pomalidomide	DMTGBAX	Approved	Protein cereblon (CRBN) increases the response to substance of Pomalidomide.	[13]
Lenalidomide	DM6Q7U4	Approved	Protein cereblon (CRBN) increases the response to substance of Lenalidomide.	[13]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein cereblon (CRBN).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein cereblon (CRBN).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein cereblon (CRBN).	[5]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein cereblon (CRBN).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein cereblon (CRBN).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein cereblon (CRBN).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein cereblon (CRBN).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein cereblon (CRBN).	[11]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein cereblon (CRBN).	[8]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology. 2004 Nov 23;63(10):1927-31. doi: 10.1212/01.wnl.0000146196.01316.a2.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [8] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Genomic and in silico analyses of CRBN gene and thalidomide embryopathy in humans. Reprod Toxicol. 2016 Dec;66:99-106. doi: 10.1016/j.reprotox.2016.10.003. Epub 2016 Oct 14.
• [13] A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple Myeloma Patient Samples. Appl Immunohistochem Mol Morphol. 2016 Nov/Dec;24(10):695-702. doi: 10.1097/PAI.0000000000000246.