Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT93UUDI)

• DOT Name: Sodium/glucose cotransporter 2 (SLC5A2)
• Synonyms: Na(+)/glucose cotransporter 2; Low affinity sodium-glucose cotransporter; Solute carrier family 5 member 2
• Gene Name: SLC5A2
• Related Disease: Familial renal glucosuria
• UniProt ID: SC5A2_HUMAN
• PDB ID: 7VSI; 7YNJ; 7YNK; 8HB0; 8HDH; 8HEZ; 8HG7; 8HIN
• Pfam ID: PF00474
• Sequence:
  MEEHTEAGSAPEMGAQKALIDNPADILVIAAYFLLVIGVGLWSMCRTNRGTVGGYFLAGR
  SMVWWPVGASLFASNIGSGHFVGLAGTGAASGLAVAGFEWNALFVVLLLGWLFAPVYLTA
  GVITMPQYLRKRFGGRRIRLYLSVLSLFLYIFTKISVDMFSGAVFIQQALGWNIYASVIA
  LLGITMIYTVTGGLAALMYTDTVQTFVILGGACILMGYAFHEVGGYSGLFDKYLGAATSL
  TVSEDPAVGNISSFCYRPRPDSYHLLRHPVTGDLPWPALLLGLTIVSGWYWCSDQVIVQR
  CLAGKSLTHIKAGCILCGYLKLTPMFLMVMPGMISRILYPDEVACVVPEVCRRVCGTEVG
  CSNIAYPRLVVKLMPNGLRGLMLAVMLAALMSSLASIFNSSSTLFTMDIYTRLRPRAGDR
  ELLLVGRLWVVFIVVVSVAWLPVVQAAQGGQLFDYIQAVSSYLAPPVSAVFVLALFVPRV
  NEQGAFWGLIGGLLMGLARLIPEFSFGSGSCVQPSACPAFLCGVHYLYFAIVLFFCSGLL
  TLTVSLCTAPIPRKHLHRLVFSLRHSKEEREDLDADEQQGSSLPVQNGCPESAMEMNEPQ
  APAPSLFRQCLLWFCGMSRGGVGSPPPLTQEEAAAAARRLEDISEDPSWARVVNLNALLM
  MAVAVFLWGFYA
• Function: Electrogenic Na(+)-coupled sugar simporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump. Has a primary role in D-glucose reabsorption from glomerular filtrate across the brush border of the early proximal tubules of the kidney.
• Reactome Pathway:
  Defective SLC5A2 causes renal glucosuria (GLYS1) (R-HSA-5658208)
  Cellular hexose transport (R-HSA-189200)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial renal glucosuria	DIS3C9XZ	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sodium/glucose cotransporter 2 (SLC5A2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sodium/glucose cotransporter 2 (SLC5A2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium/glucose cotransporter 2 (SLC5A2).	[3]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Sodium/glucose cotransporter 2 (SLC5A2).	[4]
Canagliflozin	DMFRM1I	Approved	Canagliflozin decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[5]
Bexagliflozin	DMK56G0	Approved	Bexagliflozin decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[6]
Dapagliflozin	DM28UJG	Approved	Dapagliflozin decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[5]
PF-04971729	DM79VXT	Approved	PF-04971729 decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium/glucose cotransporter 2 (SLC5A2).	[8]
Remogliflozin etabonate	DMW4YK1	Phase 2	Remogliflozin etabonate decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[5]
T-1095	DMGFS51	Discontinued in Phase 2	T-1095 decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[5]
Phlorizin	DMNARGO	Investigative	Phlorizin decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[5]
sergliflozin	DMF8GAX	Investigative	sergliflozin decreases the activity of Sodium/glucose cotransporter 2 (SLC5A2).	[5]

References

• [1] Novel SLC5A2 mutation contributes to familial renal glucosuria: Abnormal expression in renal tissues. Exp Ther Med. 2016 Aug;12(2):649-652. doi: 10.3892/etm.2016.3388. Epub 2016 May 25.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [5] Discovery of novel N--D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes. J Med Chem. 2011 Jan 13;54(1):166-78. doi: 10.1021/jm101072y. Epub 2010 Dec 3.
• [6] EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol Res. 2011 Apr;63(4):284-93. doi: 10.1016/j.phrs.2011.01.001. Epub 2011 Jan 5.
• [7] Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J Med Chem. 2011 Apr 28;54(8):2952-60. doi: 10.1021/jm200049r. Epub 2011 Mar 30.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.