Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC5SNMZ)

• DOT Name: SWI/SNF complex subunit SMARCC2 (SMARCC2)
• Synonyms: BRG1-associated factor 170; BAF170; SWI/SNF complex 170 kDa subunit; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C member 2
• Gene Name: SMARCC2
• Related Disease:
  Coffin-Siris syndrome
  Coffin-Siris syndrome 8
  Intellectual disability
  Interstitial cystitis
  Neurodevelopmental disorder
  Stomach cancer
  Gastric cancer
• UniProt ID: SMRC2_HUMAN
• PDB ID: 6KAG; 6LTH; 6LTJ; 7VDV; 7Y8R
• Pfam ID: PF00249 ; PF04433 ; PF16495 ; PF16496 ; PF16498
• Sequence:
  MAVRKKDGGPNVKYYEAADTVTQFDNVRLWLGKNYKKYIQAEPPTNKSLSSLVVQLLQFQ
  EEVFGKHVSNAPLTKLPIKCFLDFKAGGSLCHILAAAYKFKSDQGWRRYDFQNPSRMDRN
  VEMFMTIEKSLVQNNCLSRPNIFLCPEIEPKLLGKLKDIIKRHQGTVTEDKNNASHVVYP
  VPGNLEEEEWVRPVMKRDKQVLLHWGYYPDSYDTWIPASEIEASVEDAPTPEKPRKVHAK
  WILDTDTFNEWMNEEDYEVNDDKNPVSRRKKISAKTLTDEVNSPDSDRRDKKGGNYKKRK
  RSPSPSPTPEAKKKNAKKGPSTPYTKSKRGHREEEQEDLTKDMDEPSPVPNVEEVTLPKT
  VNTKKDSESAPVKGGTMTDLDEQEDESMETTGKDEDENSTGNKGEQTKNPDLHEDNVTEQ
  THHIIIPSYAAWFDYNSVHAIERRALPEFFNGKNKSKTPEIYLAYRNFMIDTYRLNPQEY
  LTSTACRRNLAGDVCAIMRVHAFLEQWGLINYQVDAESRPTPMGPPPTSHFHVLADTPSG
  LVPLQPKTPQQTSASQQMLNFPDKGKEKPTDMQNFGLRTDMYTKKNVPSKSKAAASATRE
  WTEQETLLLLEALEMYKDDWNKVSEHVGSRTQDECILHFLRLPIEDPYLEDSEASLGPLA
  YQPIPFSQSGNPVMSTVAFLASVVDPRVASAAAKSALEEFSKMKEEVPTALVEAHVRKVE
  EAAKVTGKADPAFGLESSGIAGTTSDEPERIEESGNDEARVEGQATDEKKEPKEPREGGG
  AIEEEAKEKTSEAPKKDEEKGKEGDSEKESEKSDGDPIVDPEKEKEPKEGQEEVLKEVVE
  SEGERKTKVERDIGEGNLSTAAAAALAAAAVKAKHLAAVEERKIKSLVALLVETQMKKLE
  IKLRHFEELETIMDREREALEYQRQQLLADRQAFHMEQLKYAEMRARQQHFQQMHQQQQQ
  PPPALPPGSQPIPPTGAAGPPAVHGLAVAPASVVPAPAGSGAPPGSLGPSEQIGQAGSTA
  GPQQQQPAGAPQPGAVPPGVPPPGPHGPSPFPNQQTPPSMMPGAVPGSGHPGVAGNAPLG
  LPFGMPPPPPPPAPSIIPFGSLADSISINLPAPPNLHGHHHHLPFAPGTLPPPNLPVSMA
  NPLHPNLPATTTMPSSLPLGPGLGSAAAQSPAIVAAVQGNLLPSASPLPDPGTPLPPDPT
  APSPGTVTPVPPPQ
• 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. Can stimulate the ATPase activity of the catalytic subunit of these complexes. May be required for CoREST dependent repression of neuronal specific gene promoters in non-neuronal cells. 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. Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation.
• Tissue Specificity: Ubiquitously expressed.
• 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

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 8	DISG2M6B	Definitive	Autosomal dominant	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
Interstitial cystitis	DIS7CAJA	Strong	Altered Expression	[3]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[2]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[4]
Gastric cancer	DISXGOUK	Limited	Biomarker	[4]

9 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 SWI/SNF complex subunit SMARCC2 (SMARCC2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[14]

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 SWI/SNF complex subunit SMARCC2 (SMARCC2).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of SWI/SNF complex subunit SMARCC2 (SMARCC2).	[13]

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] Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay. Am J Hum Genet. 2019 Jan 3;104(1):164-178. doi: 10.1016/j.ajhg.2018.11.007. Epub 2018 Dec 20.
• [3] Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment.Physiol Genomics. 2003 Jul 7;14(2):107-15. doi: 10.1152/physiolgenomics.00055.2003.
• [4] Plasma long noncoding RNAs PANDAR, FOXD2-AS1, and SMARCC2 as potential novel diagnostic biomarkers for gastric cancer.Cancer Manag Res. 2019 Jul 4;11:6175-6184. doi: 10.2147/CMAR.S201935. eCollection 2019.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] 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.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] 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.
• [14] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.