Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9CS413)

• DOT Name: Solute carrier family 12 member 6 (SLC12A6)
• Synonyms: Electroneutral potassium-chloride cotransporter 3; K-Cl cotransporter 3
• Gene Name: SLC12A6
• Related Disease:
  Agenesis of the corpus callosum with peripheral neuropathy
  Charcot-Marie-Tooth disease, axonal, IIa 2II
• UniProt ID: S12A6_HUMAN
• PDB ID: 6M1Y; 6M22; 6Y5R; 6Y5V; 7AIN; 7AIO; 7D90; 7NGB
• Pfam ID: PF00324 ; PF03522
• Sequence:
  MHPPETTTKMASVRFMVTPTKIDDIPGLSDTSPDLSSRSSSRVRFSSRESVPETSRSEPM
  SEMSGATTSLATVALDPPSDRTSHPQDVIEDLSQNSITGEHSQLLDDGHKKARNAYLNNS
  NYEEGDEYFDKNLALFEEEMDTRPKVSSLLNRMANYTNLTQGAKEHEEAENITEGKKKPT
  KTPQMGTFMGVYLPCLQNIFGVILFLRLTWVVGTAGVLQAFAIVLICCCCTMLTAISMSA
  IATNGVVPAGGSYFMISRALGPEFGGAVGLCFYLGTTFAAAMYILGAIEIFLVYIVPRAA
  IFHSDDALKESAAMLNNMRVYGTAFLVLMVLVVFIGVRYVNKFASLFLACVIVSILAIYA
  GAIKSSFAPPHFPVCMLGNRTLSSRHIDVCSKTKEINNMTVPSKLWGFFCNSSQFFNATC
  DEYFVHNNVTSIQGIPGLASGIITENLWSNYLPKGEIIEKPSAKSSDVLGSLNHEYVLVD
  ITTSFTLLVGIFFPSVTGIMAGSNRSGDLKDAQKSIPIGTILAILTTSFVYLSNVVLFGA
  CIEGVVLRDKFGDAVKGNLVVGTLSWPSPWVIVIGSFFSTCGAGLQSLTGAPRLLQAIAK
  DNIIPFLRVFGHSKANGEPTWALLLTAAIAELGILIASLDLVAPILSMFFLMCYLFVNLA
  CALQTLLRTPNWRPRFRYYHWALSFMGMSICLALMFISSWYYAIVAMVIAGMIYKYIEYQ
  GAEKEWGDGIRGLSLSAARFALLRLEEGPPHTKNWRPQLLVLLKLDEDLHVKHPRLLTFA
  SQLKAGKGLTIVGSVIVGNFLENYGEALAAEQTIKHLMEAEKVKGFCQLVVAAKLREGIS
  HLIQSCGLGGMKHNTVVMGWPNGWRQSEDARAWKTFIGTVRVTTAAHLALLVAKNISFFP
  SNVEQFSEGNIDVWWIVHDGGMLMLLPFLLKQHKVWRKCSIRIFTVAQLEDNSIQMKKDL
  ATFLYHLRIEAEVEVVEMHDSDISAYTYERTLMMEQRSQMLRHMRLSKTERDREAQLVKD
  RNSMLRLTSIGSDEDEETETYQEKVHMTWTKDKYMASRGQKAKSMEGFQDLLNMRPDQSN
  VRRMHTAVKLNEVIVNKSHEAKLVLLNMPGPPRNPEGDENYMEFLEVLTEGLERVLLVRG
  GGSEVITIYS
• Function: [Isoform 1]: Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells ; [Isoform 2]: Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (Probable); [Isoform 3]: Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (Probable); [Isoform 4]: Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (Probable); [Isoform 5]: Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (Probable); [Isoform 6]: Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells (Probable).
• Tissue Specificity: Expressed in brain (at protein level) . Highly expressed in heart, brain and kidney. Detected at lower levels in skeletal muscle, placenta, lung and pancreas . Detected in umbilical vein endothelial cells .; [Isoform 2]: More abundant in kidney.; [Isoform 5]: Testis specific.
• Reactome Pathway:
  Defective SLC12A6 causes agenesis of the corpus callosum, with peripheral neuropathy (ACCPN) (R-HSA-5619039)
  Cation-coupled Chloride cotransporters (R-HSA-426117)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Agenesis of the corpus callosum with peripheral neuropathy	DISMOV7L	Definitive	Autosomal recessive	[1]
Charcot-Marie-Tooth disease, axonal, IIa 2II	DISFV7SE	Strong	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Thalidomide	DM70BU5	Approved	Solute carrier family 12 member 6 (SLC12A6) increases the response to substance of Thalidomide.	[15]

12 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 Solute carrier family 12 member 6 (SLC12A6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Solute carrier family 12 member 6 (SLC12A6).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Solute carrier family 12 member 6 (SLC12A6).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Solute carrier family 12 member 6 (SLC12A6).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[10]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[13]
Oxamflatin	DM1TG3C	Terminated	Oxamflatin increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[14]
Apicidin	DM83WVF	Investigative	Apicidin increases the expression of Solute carrier family 12 member 6 (SLC12A6).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Solute carrier family 12 member 6 (SLC12A6).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Solute carrier family 12 member 6 (SLC12A6).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Solute carrier family 12 member 6 (SLC12A6).	[6]

References

• [1] The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002 Nov;32(3):384-92. doi: 10.1038/ng1002. Epub 2002 Oct 7.
• [2] Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. Sci Signal. 2016 Aug 2;9(439):ra77. doi: 10.1126/scisignal.aae0546.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] 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.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [12] 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.
• [13] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol. 2011 Mar 1;29(7):797-804. doi: 10.1200/JCO.2010.28.0792. Epub 2011 Jan 18.