Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ZJ3LH)

• DOT Name: Solute carrier family 12 member 2 (SLC12A2)
• Synonyms: Basolateral Na-K-Cl symporter; Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2
• Gene Name: SLC12A2
• Related Disease:
  Delpire-McNeill syndrome
  Hearing loss, autosomal dominant 78
  Kilquist syndrome
  Autosomal recessive non-syndromic intellectual disability
  Syndromic intellectual disability
  Schizophrenia
• UniProt ID: S12A2_HUMAN
• PDB ID: 6PZT; 7D10; 7MXO; 7N3N; 7S1X; 7S1Y; 7S1Z; 7SFL; 7SMP; 7ZGO
• Pfam ID: PF00324 ; PF08403 ; PF03522
• Sequence:
  MEPRPTAPSSGAPGLAGVGETPSAAALAAARVELPGTAVPSVPEDAAPASRDGGGVRDEG
  PAAAGDGLGRPLGPTPSQSRFQVDLVSENAGRAAAAAAAAAAAAAAAGAGAGAKQTPADG
  EASGESEPAKGSEEAKGRFRVNFVDPAASSSAEDSLSDAAGVGVDGPNVSFQNGGDTVLS
  EGSSLHSGGGGGSGHHQHYYYDTHTNTYYLRTFGHNTMDAVPRIDHYRHTAAQLGEKLLR
  PSLAELHDELEKEPFEDGFANGEESTPTRDAVVTYTAESKGVVKFGWIKGVLVRCMLNIW
  GVMLFIRLSWIVGQAGIGLSVLVIMMATVVTTITGLSTSAIATNGFVRGGGAYYLISRSL
  GPEFGGAIGLIFAFANAVAVAMYVVGFAETVVELLKEHSILMIDEINDIRIIGAITVVIL
  LGISVAGMEWEAKAQIVLLVILLLAIGDFVIGTFIPLESKKPKGFFGYKSEIFNENFGPD
  FREEETFFSVFAIFFPAATGILAGANISGDLADPQSAIPKGTLLAILITTLVYVGIAVSV
  GSCVVRDATGNVNDTIVTELTNCTSAACKLNFDFSSCESSPCSYGLMNNFQVMSMVSGFT
  PLISAGIFSATLSSALASLVSAPKIFQALCKDNIYPAFQMFAKGYGKNNEPLRGYILTFL
  IALGFILIAELNVIAPIISNFFLASYALINFSVFHASLAKSPGWRPAFKYYNMWISLLGA
  ILCCIVMFVINWWAALLTYVIVLGLYIYVTYKKPDVNWGSSTQALTYLNALQHSIRLSGV
  EDHVKNFRPQCLVMTGAPNSRPALLHLVHDFTKNVGLMICGHVHMGPRRQAMKEMSIDQA
  KYQRWLIKNKMKAFYAPVHADDLREGAQYLMQAAGLGRMKPNTLVLGFKKDWLQADMRDV
  DMYINLFHDAFDIQYGVVVIRLKEGLDISHLQGQEELLSSQEKSPGTKDVVVSVEYSKKS
  DLDTSKPLSEKPITHKVEEEDGKTATQPLLKKESKGPIVPLNVADQKLLEASTQFQKKQG
  KNTIDVWWLFDDGGLTLLIPYLLTTKKKWKDCKIRVFIGGKINRIDHDRRAMATLLSKFR
  IDFSDIMVLGDINTKPKKENIIAFEEIIEPYRLHEDDKEQDIADKMKEDEPWRITDNELE
  LYKTKTYRQIRLNELLKEHSSTANIIVMSLPVARKGAVSSALYMAWLEALSKDLPPILLV
  RGNHQSVLTFYS
• Function: Cation-chloride cotransporter which mediates the electroneutral transport of chloride, potassium and/or sodium ions across the membrane. Plays a vital role in the regulation of ionic balance and cell volume.
• Tissue Specificity: Expressed in many tissues.
• KEGG Pathway:
  Salivary secretion (hsa04970)
  Pancreatic secretion (hsa04972)
  Vibrio cholerae infection (hsa05110)
• Reactome Pathway: Cation-coupled Chloride cotransporters (R-HSA-426117)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Delpire-McNeill syndrome	DISVS76K	Strong	Autosomal dominant	[1]
Hearing loss, autosomal dominant 78	DISM9ZN0	Strong	Autosomal dominant	[2]
Kilquist syndrome	DISQGY0T	Strong	Autosomal recessive	[3]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[4]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[5]
Schizophrenia	DISSRV2N	No Known	Unknown	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Solute carrier family 12 member 2 (SLC12A2) decreases the response to substance of Paclitaxel.	[29]

2 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 Solute carrier family 12 member 2 (SLC12A2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Solute carrier family 12 member 2 (SLC12A2).	[24]

30 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 2 (SLC12A2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Solute carrier family 12 member 2 (SLC12A2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Solute carrier family 12 member 2 (SLC12A2).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Solute carrier family 12 member 2 (SLC12A2).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[13]
Estrone	DM5T6US	Approved	Estrone decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[13]
Ximelegatran	DMU8ANS	Approved	Ximelegatran increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[18]
Estriol	DMOEM2I	Approved	Estriol decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[13]
Ethacrynic acid	DM60QMR	Approved	Ethacrynic acid decreases the activity of Solute carrier family 12 member 2 (SLC12A2).	[19]
Furosemide	DMMQ8ZG	Approved	Furosemide decreases the activity of Solute carrier family 12 member 2 (SLC12A2).	[19]
Bumetanide	DMRV7H0	Approved	Bumetanide decreases the activity of Solute carrier family 12 member 2 (SLC12A2).	[19]
Torasemide	DMXKJ6C	Approved	Torasemide decreases the activity of Solute carrier family 12 member 2 (SLC12A2).	[19]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[23]
Ticrynafen	DMLFSTR	Withdrawn from market	Ticrynafen decreases the activity of Solute carrier family 12 member 2 (SLC12A2).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[25]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[26]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[27]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the expression of Solute carrier family 12 member 2 (SLC12A2).	[28]
Fasudil	DMTCNOM	Investigative	Fasudil increases the expression of Solute carrier family 12 member 2 (SLC12A2).	[18]
Piretanide	DM0SCDR	Investigative	Piretanide decreases the activity of Solute carrier family 12 member 2 (SLC12A2).	[19]

References

• [1] Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism-Epilepsy Phenotype with Macrocephaly. Neuromolecular Med. 2016 Mar;18(1):69-80. doi: 10.1007/s12017-015-8378-2. Epub 2015 Nov 4.
• [2] Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans. PLoS Genet. 2020 Apr 15;16(4):e1008643. doi: 10.1371/journal.pgen.1008643. eCollection 2020 Apr.
• [3] Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet. 1999 Jun;22(2):192-5. doi: 10.1038/9713.
• [4] SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. Brain. 2020 Aug 1;143(8):2380-2387. doi: 10.1093/brain/awaa176.
• [5] SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia. Neurol Genet. 2020 Jul 2;6(4):e478. doi: 10.1212/NXG.0000000000000478. eCollection 2020 Aug.
• [6] Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia. J Psychiatr Res. 2016 Jun;77:22-6. doi: 10.1016/j.jpsychires.2016.02.016. Epub 2016 Feb 27.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals. Environ Health Perspect. 2004 May;112(7):773-81. doi: 10.1289/ehp.6753.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Capsaicinoids regulate airway anion transporters through Rho kinase- and cyclic AMP-dependent mechanisms. Am J Respir Cell Mol Biol. 2011 Oct;45(4):684-91. doi: 10.1165/rcmb.2010-0332OC. Epub 2011 Jan 28.
• [19] Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B. Sci Rep. 2018 Jun 29;8(1):9877. doi: 10.1038/s41598-018-27995-w.
• [20] 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.
• [21] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] 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.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [27] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [28] Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett. 2005 Mar 14;579(7):1732-40.
• [29] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.