Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRT44ZG)

• DOT Name: Bromodomain-containing protein 3 (BRD3)
• Synonyms: RING3-like protein
• Gene Name: BRD3
• UniProt ID: BRD3_HUMAN
• PDB ID: 2E7N ; 2NXB ; 2OO1 ; 2YW5 ; 3S91 ; 3S92 ; 5A7C ; 5HFR ; 5HJC ; 6BGG ; 6BGH ; 6I41 ; 6I5P ; 6I68 ; 6I7A ; 6QJU ; 6U4A ; 6ULP ; 7JMY ; 7JQ8 ; 7JYN ; 7JYZ ; 7L72 ; 7L9L ; 7LAY ; 7LAZ ; 7LB4 ; 7LBT ; 7R8R ; 7RJK ; 7RJL ; 7RJM ; 7RJN ; 7S3P ; 7TO7 ; 7TO8 ; 7TO9 ; 7TOA ; 7UG5 ; 8B5A ; 8CV5
• Pfam ID: PF17035 ; PF00439
• Sequence:
  MSTATTVAPAGIPATPGPVNPPPPEVSNPSKPGRKTNQLQYMQNVVVKTLWKHQFAWPFY
  QPVDAIKLNLPDYHKIIKNPMDMGTIKKRLENNYYWSASECMQDFNTMFTNCYIYNKPTD
  DIVLMAQALEKIFLQKVAQMPQEEVELLPPAPKGKGRKPAAGAQSAGTQQVAAVSSVSPA
  TPFQSVPPTVSQTPVIAATPVPTITANVTSVPVPPAAAPPPPATPIVPVVPPTPPVVKKK
  GVKRKADTTTPTTSAITASRSESPPPLSDPKQAKVVARRESGGRPIKPPKKDLEDGEVPQ
  HAGKKGKLSEHLRYCDSILREMLSKKHAAYAWPFYKPVDAEALELHDYHDIIKHPMDLST
  VKRKMDGREYPDAQGFAADVRLMFSNCYKYNPPDHEVVAMARKLQDVFEMRFAKMPDEPV
  EAPALPAPAAPMVSKGAESSRSSEESSSDSGSSDSEEERATRLAELQEQLKAVHEQLAAL
  SQAPVNKPKKKKEKKEKEKKKKDKEKEKEKHKVKAEEEKKAKVAPPAKQAQQKKAPAKKA
  NSTTTAGRQLKKGGKQASASYDSEEEEEGLPMSYDEKRQLSLDINRLPGEKLGRVVHIIQ
  SREPSLRDSNPDEIEIDFETLKPTTLRELERYVKSCLQKKQRKPFSASGKKQAAKSKEEL
  AQEKKKELEKRLQDVSGQLSSSKKPARKEKPGSAPSGGPSRLSSSSSSESGSSSSSGSSS
  DSSDSE
• Function: Chromatin reader that recognizes and binds acetylated histones, 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. In vitro, binds acetylated lysine residues on the N-terminus of histone H2A, H2B, H3 and H4. Involved in endoderm differentiation via its association with long non-coding RNA (lncRNA) DIGIT: BRD3 undergoes liquid-liquid phase separation upon binding to lncRNA DIGIT, promoting binding to histone H3 acetylated at 'Lys-18' (H3K18ac) to induce endoderm gene expression. Also binds non-histones acetylated proteins, such as GATA1 and GATA2: regulates transcription by promoting the binding of the transcription factor GATA1 to its targets.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Bromodomain-containing protein 3 (BRD3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Bromodomain-containing protein 3 (BRD3).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Bromodomain-containing protein 3 (BRD3).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Bromodomain-containing protein 3 (BRD3).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Bromodomain-containing protein 3 (BRD3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bromodomain-containing protein 3 (BRD3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bromodomain-containing protein 3 (BRD3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bromodomain-containing protein 3 (BRD3).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bromodomain-containing protein 3 (BRD3).	[5]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Bromodomain-containing protein 3 (BRD3).	[3]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Bromodomain-containing protein 3 (BRD3).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Bromodomain-containing protein 3 (BRD3).	[8]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Bromodomain-containing protein 3 (BRD3).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Bromodomain-containing protein 3 (BRD3).	[12]

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] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int J Cancer. 2016 Nov 1;139(9):2047-55. doi: 10.1002/ijc.30256. Epub 2016 Jul 30.
• [7] 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.
• [8] 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.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] 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.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] 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.