Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT68WOPQ)

• DOT Name: Transcription activator BRG1 (SMARCA4)
• Synonyms: EC 3.6.4.-; ATP-dependent helicase SMARCA4; BRG1-associated factor 190A; BAF190A; Mitotic growth and transcription activator; Protein BRG-1; Protein brahma homolog 1; SNF2-beta; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4
• Gene Name: SMARCA4
• Related Disease:
  Coffin-Siris syndrome
  Coffin-Siris syndrome 1
  Rhabdoid tumor predisposition syndrome 2
  Intellectual disability, autosomal dominant 16
  Uterine corpus sarcoma
  Familial rhabdoid tumor
  Hereditary nonpolyposis colon cancer
• UniProt ID: SMCA4_HUMAN
• PDB ID: 2GRC; 2H60; 3UVD; 5DKD; 5EA1; 6BGH; 6HR2; 6LTH; 6LTJ; 6SY2; 6ZS2; 7TAB; 7VDT; 7VDV; 7VRB; 7Y8R; 8EB1; 8G1Q
• EC Number: 3.6.4.-
• Pfam ID: PF07533 ; PF00439 ; PF00271 ; PF07529 ; PF08880 ; PF14619 ; PF00176
• Sequence:
  MSTPDPPLGGTPRPGPSPGPGPSPGAMLGPSPGPSPGSAHSMMGPSPGPPSAGHPIPTQG
  PGGYPQDNMHQMHKPMESMHEKGMSDDPRYNQMKGMGMRSGGHAGMGPPPSPMDQHSQGY
  PSPLGGSEHASSPVPASGPSSGPQMSSGPGGAPLDGADPQALGQQNRGPTPFNQNQLHQL
  RAQIMAYKMLARGQPLPDHLQMAVQGKRPMPGMQQQMPTLPPPSVSATGPGPGPGPGPGP
  GPGPAPPNYSRPHGMGGPNMPPPGPSGVPPGMPGQPPGGPPKPWPEGPMANAAAPTSTPQ
  KLIPPQPTGRPSPAPPAVPPAASPVMPPQTQSPGQPAQPAPMVPLHQKQSRITPIQKPRG
  LDPVEILQEREYRLQARIAHRIQELENLPGSLAGDLRTKATIELKALRLLNFQRQLRQEV
  VVCMRRDTALETALNAKAYKRSKRQSLREARITEKLEKQQKIEQERKRRQKHQEYLNSIL
  QHAKDFKEYHRSVTGKIQKLTKAVATYHANTEREQKKENERIEKERMRRLMAEDEEGYRK
  LIDQKKDKRLAYLLQQTDEYVANLTELVRQHKAAQVAKEKKKKKKKKKAENAEGQTPAIG
  PDGEPLDETSQMSDLPVKVIHVESGKILTGTDAPKAGQLEAWLEMNPGYEVAPRSDSEES
  GSEEEEEEEEEEQPQAAQPPTLPVEEKKKIPDPDSDDVSEVDARHIIENAKQDVDDEYGV
  SQALARGLQSYYAVAHAVTERVDKQSALMVNGVLKQYQIKGLEWLVSLYNNNLNGILADE
  MGLGKTIQTIALITYLMEHKRINGPFLIIVPLSTLSNWAYEFDKWAPSVVKVSYKGSPAA
  RRAFVPQLRSGKFNVLLTTYEYIIKDKHILAKIRWKYMIVDEGHRMKNHHCKLTQVLNTH
  YVAPRRLLLTGTPLQNKLPELWALLNFLLPTIFKSCSTFEQWFNAPFAMTGEKVDLNEEE
  TILIIRRLHKVLRPFLLRRLKKEVEAQLPEKVEYVIKCDMSALQRVLYRHMQAKGVLLTD
  GSEKDKKGKGGTKTLMNTIMQLRKICNHPYMFQHIEESFSEHLGFTGGIVQGLDLYRASG
  KFELLDRILPKLRATNHKVLLFCQMTSLMTIMEDYFAYRGFKYLRLDGTTKAEDRGMLLK
  TFNEPGSEYFIFLLSTRAGGLGLNLQSADTVIIFDSDWNPHQDLQAQDRAHRIGQQNEVR
  VLRLCTVNSVEEKILAAAKYKLNVDQKVIQAGMFDQKSSSHERRAFLQAILEHEEQDESR
  HCSTGSGSASFAHTAPPPAGVNPDLEEPPLKEEDEVPDDETVNQMIARHEEEFDLFMRMD
  LDRRREEARNPKRKPRLMEEDELPSWIIKDDAEVERLTCEEEEEKMFGRGSRHRKEVDYS
  DSLTEKQWLKAIEEGTLEEIEEEVRQKKSSRKRKRDSDAGSSTPTTSTRSRDKDDESKKQ
  KKRGRPPAEKLSPNPPNLTKKMKKIVDAVIKYKDSSSGRQLSEVFIQLPSRKELPEYYEL
  IRKPVDFKKIKERIRNHKYRSLNDLEKDVMLLCQNAQTFNLEGSLIYEDSIVLQSVFTSV
  RQKIEKEDDSEGEESEEEEEGEEEGSESESRSVKVKIKLGRKEKAQDRLKGGRRRPSRGS
  RAKPVVSDDDSEEEQEEDRSGSGSEED
• Function: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating the calcium-dependent release of a repressor complex and the recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by SMARCA4-dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves the release of HDAC1 and recruitment of CREBBP. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development, a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues. Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial-mesenchymal transition (EMT) by ZEB1. Binds via DLX1 to enhancers located in the intergenic region between DLX5 and DLX6 and this binding is stabilized by the long non-coding RNA (lncRNA) Evf2. Binds to RNA in a promiscuous manner. Binding to RNAs including lncRNA Evf2 leads to inhibition of SMARCA4 ATPase and chromatin remodeling activities. In brown adipose tissue, involved in the regulation of thermogenic genes expression.
• Tissue Specificity: Colocalizes with ZEB1 in E-cadherin-negative cells from established lines, and stroma of normal colon as well as in de-differentiated epithelial cells at the invasion front of colorectal carcinomas (at protein level).
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  Formation of the beta-catenin (R-HSA-201722)
  RMTs methylate histone arginines (R-HSA-3214858)
  Chromatin modifying enzymes (R-HSA-3247509)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)
  Interleukin-7 signaling (R-HSA-1266695)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coffin-Siris syndrome	DIS8L03H	Definitive	Autosomal dominant	[1]
Coffin-Siris syndrome 1	DIS95FRP	Definitive	Autosomal dominant	[2]
Rhabdoid tumor predisposition syndrome 2	DISVN4LS	Definitive	Autosomal dominant	[1]
Intellectual disability, autosomal dominant 16	DIS3L7HA	Strong	Autosomal dominant	[3]
Uterine corpus sarcoma	DIS502ED	Moderate	Autosomal recessive	[4]
Familial rhabdoid tumor	DISC6GHQ	Supportive	Autosomal dominant	[5]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Transcription activator BRG1 (SMARCA4) affects the response to substance of Topotecan.	[25]

8 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 Transcription activator BRG1 (SMARCA4).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Transcription activator BRG1 (SMARCA4).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Transcription activator BRG1 (SMARCA4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transcription activator BRG1 (SMARCA4).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Transcription activator BRG1 (SMARCA4).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcription activator BRG1 (SMARCA4).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Transcription activator BRG1 (SMARCA4).	[14]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Transcription activator BRG1 (SMARCA4).	[24]

15 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 Transcription activator BRG1 (SMARCA4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription activator BRG1 (SMARCA4).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription activator BRG1 (SMARCA4).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcription activator BRG1 (SMARCA4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transcription activator BRG1 (SMARCA4).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcription activator BRG1 (SMARCA4).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcription activator BRG1 (SMARCA4).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Transcription activator BRG1 (SMARCA4).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transcription activator BRG1 (SMARCA4).	[17]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transcription activator BRG1 (SMARCA4).	[18]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Transcription activator BRG1 (SMARCA4).	[19]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Transcription activator BRG1 (SMARCA4).	[20]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Transcription activator BRG1 (SMARCA4).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Transcription activator BRG1 (SMARCA4).	[11]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Transcription activator BRG1 (SMARCA4).	[23]

References

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• [4] SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association. Mod Pathol. 2019 Nov;32(11):1675-1687. doi: 10.1038/s41379-019-0303-z. Epub 2019 Jun 12.
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• [14] 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.
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• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] 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.
• [19] Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex. Br J Cancer. 2013 Nov 12;109(10):2751-62. doi: 10.1038/bjc.2013.583. Epub 2013 Oct 29.
• [20] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [21] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [22] 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.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [24] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
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