Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWE6180)

• DOT Name: Integrator complex subunit 13 (INTS13)
• Synonyms: Cell cycle regulator Mat89Bb homolog; Germ cell tumor 1; Protein asunder homolog; Sarcoma antigen NY-SAR-95
• Gene Name: INTS13
• Related Disease:
  Tuberculosis
  Seminoma
  Dedifferentiated liposarcoma
  Desmoid tumour
  Gastrointestinal stromal tumour
  Gonorrhea
  Granulosa cell tumor
  Neoplasm
  Ovarian granulosa cell tumor
• UniProt ID: INT13_HUMAN
• PDB ID: 6SN1
• Pfam ID: PF10221
• Sequence:
  MKIFSESHKTVFVVDHCPYMAESCRQHVEFDMLVKNRTQGIIPLAPISKSLWTCSVESSM
  EYCRIMYDIFPFKKLVNFIVSDSGAHVLNSWTQEDQNLQELMAALAAVGPPNPRADPECC
  SILHGLVAAVETLCKITEYQHEARTLLMENAERVGNRGRIICITNAKSDSHVRMLEDCVQ
  ETIHEHNKLAANSDHLMQIQKCELVLIHTYPVGEDSLVSDRSKKELSPVLTSEVHSVRAG
  RHLATKLNILVQQHFDLASTTITNIPMKEEQHANTSANYDVELLHHKDAHVDFLKSGDSH
  LGGGSREGSFKETITLKWCTPRTNNIELHYCTGAYRISPVDVNSRPSSCLTNFLLNGRSV
  LLEQPRKSGSKVISHMLSSHGGEIFLHVLSSSRSILEDPPSISEGCGGRVTDYRITDFGE
  FMRENRLTPFLDPRYKIDGSLEVPLERAKDQLEKHTRYWPMIISQTTIFNMQAVVPLASV
  IVKESLTEEDVLNCQKTIYNLVDMERKNDPLPISTVGTRGKGPKRDEQYRIMWNELETLV
  RAHINNSEKHQRVLECLMACRSKPPEEEERKKRGRKREDKEDKSEKAVKDYEQEKSWQDS
  ERLKGILERGKEELAEAEIIKDSPDSPEPPNKKPLVEMDETPQVEKSKGPVSLLSLWSNR
  INTANSRKHQEFAGRLNSVNNRAELYQHLKEENGMETTENGKASRQ
• Function: Crucial regulator of the mitotic cell cycle and development. At prophase, required for dynein anchoring to the nuclear envelope important for proper centrosome-nucleus coupling. At G2/M phase, may be required for proper spindle formation and execution of cytokinesis. Probable component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing.
• Tissue Specificity: Widely expressed. Tends to be up-regulated in seminomas compared to normal testis.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[1]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[2]
Dedifferentiated liposarcoma	DISYJUCJ	Limited	Biomarker	[3]
Desmoid tumour	DISGX357	Limited	Biomarker	[3]
Gastrointestinal stromal tumour	DIS6TJYS	Limited	Biomarker	[3]
Gonorrhea	DISQ5AO6	Limited	Biomarker	[4]
Granulosa cell tumor	DISKWVAB	Limited	Genetic Variation	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]
Ovarian granulosa cell tumor	DISRVQAA	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Integrator complex subunit 13 (INTS13).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Integrator complex subunit 13 (INTS13).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Integrator complex subunit 13 (INTS13).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrator complex subunit 13 (INTS13).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Integrator complex subunit 13 (INTS13).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Integrator complex subunit 13 (INTS13).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Integrator complex subunit 13 (INTS13).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Integrator complex subunit 13 (INTS13).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Integrator complex subunit 13 (INTS13).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Integrator complex subunit 13 (INTS13).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Integrator complex subunit 13 (INTS13).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Integrator complex subunit 13 (INTS13).	[12]

References

• [1] Gene expression profiling identifies candidate biomarkers for active and latent tuberculosis.BMC Bioinformatics. 2016 Jan 11;17 Suppl 1(Suppl 1):3. doi: 10.1186/s12859-015-0848-x.
• [2] Genomic and expression analysis of the 12p11-p12 amplicon using EST arrays identifies two novel amplified and overexpressed genes.Cancer Res. 2002 Nov 1;62(21):6218-23.
• [3] Management and outcomes of ruptured, perforated or fistulized tumors of mesenchymal origin.J Surg Oncol. 2020 Mar;121(3):474-479. doi: 10.1002/jso.25807. Epub 2019 Dec 17.
• [4] Fine map of the Gct1 spontaneous ovarian granulosa cell tumor locus.Mamm Genome. 2013 Feb;24(1-2):63-71. doi: 10.1007/s00335-012-9439-6. Epub 2012 Nov 18.
• [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] 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.
• [7] 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.
• [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] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [11] 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.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.