Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0C202)

• DOT Name: Transmembrane 9 superfamily member 2 (TM9SF2)
• Synonyms: p76
• Gene Name: TM9SF2
• Related Disease:
  Chikungunya virus infection
  Colorectal carcinoma
  Neoplasm
  Pancreatic adenocarcinoma
• UniProt ID: TM9S2_HUMAN
• Pfam ID: PF02990
• Sequence:
  MSARLPVLSPPRWPRLLLLSLLLLGAVPGPRRSGAFYLPGLAPVNFCDEEKKSDECKAEI
  ELFVNRLDSVESVLPYEYTAFDFCQASEGKRPSENLGQVLFGERIEPSPYKFTFNKKETC
  KLVCTKTYHTEKAEDKQKLEFLKKSMLLNYQHHWIVDNMPVTWCYDVEDGQRFCNPGFPI
  GCYITDKGHAKDACVISSDFHERDTFYIFNHVDIKIYYHVVETGSMGARLVAAKLEPKSF
  KHTHIDKPDCSGPPMDISNKASGEIKIAYTYSVSFEEDDKIRWASRWDYILESMPHTHIQ
  WFSIMNSLVIVLFLSGMVAMIMLRTLHKDIARYNQMDSTEDAQEEFGWKLVHGDIFRPPR
  KGMLLSVFLGSGTQILIMTFVTLFFACLGFLSPANRGALMTCAVVLWVLLGTPAGYVAAR
  FYKSFGGEKWKTNVLLTSFLCPGIVFADFFIMNLILWGEGSSAAIPFGTLVAILALWFCI
  SVPLTFIGAYFGFKKNAIEHPVRTNQIPRQIPEQSFYTKPLPGIIMGGILPFGCIFIQLF
  FILNSIWSHQMYYMFGFLFLVFIILVITCSEATILLCYFHLCAEDYHWQWRSFLTSGFTA
  VYFLIYAVHYFFSKLQITGTASTILYFGYTMIMVLIFFLFTGTIGFFACFWFVTKIYSVV
  KVD
• Function: In the intracellular compartments, may function as a channel or small molecule transporter.
• Tissue Specificity: Ubiquitously expressed. Especially abundant in pancreas, highly expressed in kidney, lower levels in heart, brain, skeletal muscle and placenta. Lowest expression in lung and liver.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[12]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[12]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[14]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Transmembrane 9 superfamily member 2 (TM9SF2).	[15]

References

• [1] Genome-Wide Screening Uncovers the Significance of N-Sulfation of Heparan Sulfate as a Host Cell Factor for Chikungunya Virus Infection.J Virol. 2017 Jun 9;91(13):e00432-17. doi: 10.1128/JVI.00432-17. Print 2017 Jul 1.
• [2] Transposon mutagenesis screen in mice identifies TM9SF2 as a novel colorectal cancer oncogene.Sci Rep. 2018 Oct 17;8(1):15327. doi: 10.1038/s41598-018-33527-3.
• [3] LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2.Cell Death Dis. 2019 Sep 20;10(10):698. doi: 10.1038/s41419-019-1896-3.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [15] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.