Details of Drug Off-Target (DOT)

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

• DOT Name: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2)
• Synonyms: 60 kDa BRG-1/Brm-associated factor subunit B; BRG1-associated factor 60B; BAF60B
• Gene Name: SMARCD2
• Related Disease:
  Acute myelogenous leukaemia
  Myeloid leukaemia
  Specific granule deficiency 1
  leukaemia
  Leukemia
  Neoplasm
  Specific granule deficiency 2
  Specific granule deficiency
• UniProt ID: SMRD2_HUMAN
• Pfam ID: PF02201
• Sequence:
  MSGRGAGGFPLPPLSPGGGAVAAALGAPPPPAGPGMLPGPALRGPGPAGGVGGPGAAAFR
  PMGPAGPAAQYQRPGMSPGNRMPMAGLQVGPPAGSPFGAAAPLRPGMPPTMMDPFRKRLL
  VPQAQPPMPAQRRGLKRRKMADKVLPQRIRELVPESQAYMDLLAFERKLDQTIARKRMEI
  QEAIKKPLTQKRKLRIYISNTFSPSKAEGDSAGTAGTPGGTPAGDKVASWELRVEGKLLD
  DPSKQKRKFSSFFKSLVIELDKELYGPDNHLVEWHRMPTTQETDGFQVKRPGDLNVKCTL
  LLMLDHQPPQYKLDPRLARLLGVHTQTRAAIMQALWLYIKHNQLQDGHEREYINCNRYFR
  QIFSCGRLRFSEIPMKLAGLLQHPDPIVINHVISVDPNDQKKTACYDIDVEVDDPLKAQM
  SNFLASTTNQQEIASLDVKIHETIESINQLKTQRDFMLSFSTDPQDFIQEWLRSQRRDLK
  IITDVIGNPEEERRAAFYHQPWAQEAVGRHIFAKVQQRRQELEQVLGIRLT
• 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. Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation.
• Tissue Specificity: Isoform 2 is expressed in the pancreas.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  RMTs methylate histone arginines (R-HSA-3214858)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Myeloid leukaemia	DISMN944	Definitive	Biomarker	[2]
Specific granule deficiency 1	DISL32CF	Definitive	GermlineCausalMutation	[2]
leukaemia	DISS7D1V	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Specific granule deficiency 2	DIS4H1XW	Strong	Autosomal recessive	[2]
Specific granule deficiency	DISXJ6Y2	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[16]

10 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 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 (SMARCD2).	[15]

References

• [1] SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia.Mol Cancer Res. 2018 May;16(5):791-804. doi: 10.1158/1541-7786.MCR-17-0493. Epub 2018 Feb 26.
• [2] Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes. Nat Genet. 2017 May;49(5):742-752. doi: 10.1038/ng.3833. Epub 2017 Apr 3.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [10] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [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.