Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXBIYO8)

• DOT Name: Sphingosine 1-phosphate receptor 3 (S1PR3)
• Synonyms: S1P receptor 3; S1P3; Endothelial differentiation G-protein coupled receptor 3; Sphingosine 1-phosphate receptor Edg-3; S1P receptor Edg-3
• Gene Name: S1PR3
• UniProt ID: S1PR3_HUMAN
• PDB ID: 7C4S; 7EW2; 7EW3; 7EW4
• Pfam ID: PF00001
• Sequence:
  MATALPPRLQPVRGNETLREHYQYVGKLAGRLKEASEGSTLTTVLFLVICSFIVLENLMV
  LIAIWKNNKFHNRMYFFIGNLALCDLLAGIAYKVNILMSGKKTFSLSPTVWFLREGSMFV
  ALGASTCSLLAIAIERHLTMIKMRPYDANKRHRVFLLIGMCWLIAFTLGALPILGWNCLH
  NLPDCSTILPLYSKKYIAFCISIFTAILVTIVILYARIYFLVKSSSRKVANHNNSERSMA
  LLRTVVIVVSVFIACWSPLFILFLIDVACRVQACPILFKAQWFIVLAVLNSAMNPVIYTL
  ASKEMRRAFFRLVCNCLVRGRGARASPIQPALDPSRSKSSSSNNSSHSPKVKEDLPHTAP
  SSCIMDKNAALQNGIFCN
• Function: Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis.
• Tissue Specificity: Expressed in all tissues, but most abundantly in heart, placenta, kidney, and liver.
• KEGG Pathway:
  Sphingolipid sig.ling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Lysosphingolipid and LPA receptors (R-HSA-419408)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Sphingosine 1-phosphate receptor 3 (S1PR3) affects the response to substance of Temozolomide.	[20]
DTI-015	DMXZRW0	Approved	Sphingosine 1-phosphate receptor 3 (S1PR3) affects the response to substance of DTI-015.	[20]

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 Sphingosine 1-phosphate receptor 3 (S1PR3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sphingosine 1-phosphate receptor 3 (S1PR3).	[15]

23 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 Sphingosine 1-phosphate receptor 3 (S1PR3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[11]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[12]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[8]
Sphingosine-1-Phosphate	DMJCQKA	Phase 1	Sphingosine-1-Phosphate increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[16]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[7]
Propanoic Acid	DM9TN2W	Investigative	Propanoic Acid increases the expression of Sphingosine 1-phosphate receptor 3 (S1PR3).	[19]

References

• [1] 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.
• [2] 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.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [11] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [12] Induction of scavenger receptor class B type I is critical for simvastatin enhancement of high-density lipoprotein-induced anti-inflammatory actions in endothelial cells. J Immunol. 2008 Nov 15;181(10):7332-40. doi: 10.4049/jimmunol.181.10.7332.
• [13] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] A natural piper-amide-like compound NED-135 exhibits a potent inhibitory effect on the invasive breast cancer cells. Chem Biol Interact. 2015 Jul 25;237:58-65. doi: 10.1016/j.cbi.2015.05.006. Epub 2015 May 14.
• [17] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Propionic acid induces mitochondrial dysfunction and affects gene expression for mitochondria biogenesis and neuronal differentiation in SH-SY5Y cell line. Neurotoxicology. 2019 Dec;75:116-122. doi: 10.1016/j.neuro.2019.09.009. Epub 2019 Sep 14.
• [20] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.