Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQP2MVJ)

• DOT Name: Bromodomain-containing protein 2 (BRD2)
• Synonyms: O27.1.1
• Gene Name: BRD2
• UniProt ID: BRD2_HUMAN
• PDB ID: 1X0J ; 2DVQ ; 2DVR ; 2DVS ; 2DVV ; 2E3K ; 2G4A ; 2YDW ; 2YEK ; 3AQA ; 3ONI ; 4A9E ; 4A9F ; 4A9H ; 4A9I ; 4A9J ; 4A9M ; 4A9N ; 4A9O ; 4AKN ; 4ALG ; 4ALH ; 4J1P ; 4MR5 ; 4MR6 ; 4QEU ; 4QEV ; 4QEW ; 4UYF ; 4UYG ; 4UYH ; 5BT5 ; 5DFB ; 5DFC ; 5DFD ; 5DW1 ; 5EK9 ; 5HEL ; 5HEM ; 5HEN ; 5HFQ ; 5IBN ; 5IG6 ; 5N2L ; 5O38 ; 5O39 ; 5O3A ; 5O3B ; 5O3C ; 5O3D ; 5O3E ; 5O3F ; 5O3G ; 5O3H ; 5O3I ; 5S9O ; 5U5S ; 5U6V ; 5UEW ; 5XHE ; 5XHK ; 6CUI ; 6DB0 ; 6DBC ; 6DDI ; 6DDJ ; 6E6J ; 6FFE ; 6FFF ; 6FFG ; 6I80 ; 6I81 ; 6JKE ; 6K04 ; 6K05 ; 6MO7 ; 6MO8 ; 6MO9 ; 6MOA ; 6ONY ; 6SWO ; 6SWP ; 6TQ1 ; 6TQ2 ; 6U61 ; 6U71 ; 6U8H ; 6ULQ ; 6ULT ; 6VIY ; 6WWB ; 6YTM ; 6Z7F ; 6Z8P ; 6ZB0 ; 6ZB1 ; 6ZB2 ; 7DPN ; 7DPO ; 7ENV ; 7ENZ ; 7EO5 ; 7JX7 ; 7L6D ; 7L9G ; 7L9J ; 7L9K ; 7LAK ; 7NPY ; 7NPZ ; 7NQ0 ; 7NQ1 ; 7NQ2 ; 7NQ3 ; 7NQ5 ; 7NQ7 ; 7NQ8 ; 7NQ9 ; 7NQI ; 7NQJ ; 7OE4 ; 7OE5 ; 7OE6 ; 7OE8 ; 7OE9 ; 7OEP ; 7OER ; 7OES ; 7OET ; 7OGY ; 7Q5O ; 7USG ; 7USH ; 7USI ; 7UU0 ; 7VRH ; 7VRI ; 7VRK ; 7VRM ; 7VRO ; 7VRQ ; 7VRZ ; 7VS0 ; 7VS1 ; 7VSF ; 7WLN ; 7WMQ ; 7WMU ; 7WN5 ; 7WNA ; 7WNI ; 8B5G ; 8B5H ; 8B5I ; 8B5J ; 8CV7 ; 8PX2 ; 8PX8 ; 8SB6
• Pfam ID: PF17035 ; PF00439
• Sequence:
  MLQNVTPHNKLPGEGNAGLLGLGPEAAAPGKRIRKPSLLYEGFESPTMASVPALQLTPAN
  PPPPEVSNPKKPGRVTNQLQYLHKVVMKALWKHQFAWPFRQPVDAVKLGLPDYHKIIKQP
  MDMGTIKRRLENNYYWAASECMQDFNTMFTNCYIYNKPTDDIVLMAQTLEKIFLQKVASM
  PQEEQELVVTIPKNSHKKGAKLAALQGSVTSAHQVPAVSSVSHTALYTPPPEIPTTVLNI
  PHPSVISSPLLKSLHSAGPPLLAVTAAPPAQPLAKKKGVKRKADTTTPTPTAILAPGSPA
  SPPGSLEPKAARLPPMRRESGRPIKPPRKDLPDSQQQHQSSKKGKLSEQLKHCNGILKEL
  LSKKHAAYAWPFYKPVDASALGLHDYHDIIKHPMDLSTVKRKMENRDYRDAQEFAADVRL
  MFSNCYKYNPPDHDVVAMARKLQDVFEFRYAKMPDEPLEPGPLPVSTAMPPGLAKSSSES
  SSEESSSESSSEEEEEEDEEDEEEEESESSDSEEERAHRLAELQEQLRAVHEQLAALSQG
  PISKPKRKREKKEKKKKRKAEKHRGRAGADEDDKGPRAPRPPQPKKSKKASGSGGGSAAL
  GPSGFGPSGGSGTKLPKKATKTAPPALPTGYDSEEEEESRPMSYDEKRQLSLDINKLPGE
  KLGRVVHIIQAREPSLRDSNPEEIEIDFETLKPSTLRELERYVLSCLRKKPRKPYTIKKP
  VGKTKEELALEKKRELEKRLQDVSGQLNSTKKPPKKANEKTESSSAQQVAVSRLSASSSS
  SDSSSSSSSSSSSDTSDSDSG
• Function: Chromatin reader protein that specifically recognizes and binds histone H4 acetylated at 'Lys-5' and 'Lys-12' (H4K5ac and H4K12ac, respectively), thereby controlling gene expression and remodeling chromatin structures. Recruits transcription factors and coactivators to target gene sites, and activates RNA polymerase II machinery for transcriptional elongation. Plays a key role in genome compartmentalization via its association with CTCF and cohesin: recruited to chromatin by CTCF and promotes formation of topologically associating domains (TADs) via its ability to bind acetylated histones, contributing to CTCF boundary formation and enhancer insulation. Also recognizes and binds acetylated non-histone proteins, such as STAT3. Involved in inflammatory response by regulating differentiation of naive CD4(+) T-cells into T-helper Th17: recognizes and binds STAT3 acetylated at 'Lys-87', promoting STAT3 recruitment to chromatin. In addition to acetylated lysines, also recognizes and binds lysine residues on histones that are both methylated and acetylated on the same side chain to form N6-acetyl-N6-methyllysine (Kacme), an epigenetic mark of active chromatin associated with increased transcriptional initiation. Specifically binds histone H4 acetyl-methylated at 'Lys-5' and 'Lys-12' (H4K5acme and H4K12acme, respectively).
• Reactome Pathway: RUNX3 regulates p14-ARF (R-HSA-8951936)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Bromodomain-containing protein 2 (BRD2) decreases the response to substance of Afimoxifene.	[21]

23 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 Bromodomain-containing protein 2 (BRD2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bromodomain-containing protein 2 (BRD2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bromodomain-containing protein 2 (BRD2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Bromodomain-containing protein 2 (BRD2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Bromodomain-containing protein 2 (BRD2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bromodomain-containing protein 2 (BRD2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Bromodomain-containing protein 2 (BRD2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bromodomain-containing protein 2 (BRD2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Bromodomain-containing protein 2 (BRD2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Bromodomain-containing protein 2 (BRD2).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Bromodomain-containing protein 2 (BRD2).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Bromodomain-containing protein 2 (BRD2).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Bromodomain-containing protein 2 (BRD2).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Bromodomain-containing protein 2 (BRD2).	[6]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Bromodomain-containing protein 2 (BRD2).	[6]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Bromodomain-containing protein 2 (BRD2).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Bromodomain-containing protein 2 (BRD2).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Bromodomain-containing protein 2 (BRD2).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Bromodomain-containing protein 2 (BRD2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Bromodomain-containing protein 2 (BRD2).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Bromodomain-containing protein 2 (BRD2).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Bromodomain-containing protein 2 (BRD2).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Bromodomain-containing protein 2 (BRD2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Bromodomain-containing protein 2 (BRD2).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Bromodomain-containing protein 2 (BRD2).	[16]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [7] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] 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.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10;6(19):17698-712. doi: 10.18632/oncotarget.4131.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.