Target Information

Target General Infomation
Target ID
T13852
Former ID
TTDC00258
Target Name
Sphingosine 1-phosphate receptor 1
Gene Name
S1PR1
Synonyms
Endothelial differentiation G-protein coupled receptor 1; S1P receptor 1; S1P receptor Edg-1; S1P1; Sphingosine 1-phosphate receptor Edg-1; S1PR1
Target Type
Successful
Disease Autoimmune diabetes [ICD10: E08-E13]
Acne vulgaris [ICD9: 706.1; ICD10: L70.0]
Advanced non-small cell lung cancer [ICD9: 162; ICD10: C33-C34]
Cutaneous lupus erythematosus [ICD9: 710; ICD10: M32]
Cardiovascular disorder [ICD10: I00-I99]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hepatocellular carcinoma; Multiple scierosis [ICD9:155, 340; ICD10: C22.0, G35]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Immune disorder [ICD10: D80-D89]
Macular degeneration [ICD9: 362.5; ICD10: H35.3]
Multiple scierosis [ICD9: 340; ICD10: G35]
Psoriasis [ICD9: 696; ICD10: L40]
Primary progressive multiple sclerosis [ICD9: 340; ICD10: G35]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Function
G-protein coupled receptorfor the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 andMAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization andbone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3- phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury.
BioChemical Class
GPCR rhodopsin
Target Validation
T13852
UniProt ID
P21453
Sequence
MGPTSVPLVKAHRSSVSDYVNYDIIVRHYNYTGKLNISADKENSIKLTSVVFILICCFII
LENIFVLLTIWKTKKFHRPMYYFIGNLALSDLLAGVAYTANLLLSGATTYKLTPAQWFLR
EGSMFVALSASVFSLLAIAIERYITMLKMKLHNGSNNFRLFLLISACWVISLILGGLPIM
GWNCISALSSCSTVLPLYHKHYILFCTTVFTLLLLSIVILYCRIYSLVRTRSRRLTFRKN
ISKASRSSEKSLALLKTVIIVLSVFIACWAPLFILLLLDVGCKVKTCDILFRAEYFLVLA
VLNSGTNPIIYTLTNKEMRRAFIRIMSCCKCPSGDSAGKFKRPIIAGMEFSRSKSDNSSH
PQKDEGDNPETIMSSGNVNSSS
Drugs and Mode of Action
Drug(s) Fingolimod Drug Info Approved Primary progressive multiple sclerosis [531351], [539536]
BAF312 Drug Info Phase 3 Hepatocellular carcinoma; Multiple scierosis [524022]
RPC-1063 Drug Info Phase 3 Advanced non-small cell lung cancer [525004]
Sphingosine-1-phosphate receptor-1 agonist Drug Info Phase 3 Immune disorder [551791]
ACT-128800 Drug Info Phase 2 Psoriasis [522598]
KRP-203 Drug Info Phase 2 Cutaneous lupus erythematosus [523356]
MT-1303 Drug Info Phase 2 Multiple scierosis [524345]
ONO-4641 Drug Info Phase 2 Rheumatoid arthritis [523225]
ASP-4058 Drug Info Phase 1 Multiple scierosis [533005]
CS-0777 Drug Info Phase 1 Multiple scierosis [522226]
GSK-2018682 Drug Info Phase 1 Immune disorder [523536]
Sonepcizumab Drug Info Phase 1 Macular degeneration [522296]
Sphingosine-1-phosphate Drug Info Phase 1 Acne vulgaris [523681], [543301]
PF-4629991 Drug Info Discontinued in Phase 1 Rheumatoid arthritis [548892]
XL-541 Drug Info Terminated Cancer [548837]
Inhibitor (3-Tetradecylamino-cyclohexyl)-phosphonic acid Drug Info [527193]
(3-Tetradecylamino-cyclopentyl)-phosphonic acid Drug Info [527193]
(S)-FTY720P Drug Info [530125]
1-(4-nonylbenzyl)azetidine-3-carboxylic acid Drug Info [527349]
1-(4-nonylbenzyl)pyrrolidin-3-ylphosphonic acid Drug Info [527349]
1-(4-nonylbenzyl)pyrrolidine-3-carboxylic acid Drug Info [527349]
3-(N-alkylamino) propylphosphonic acid derivative Drug Info [527193]
3-(tetradecylamino)propylphosphonic acid Drug Info [527349]
3-amino-5-(4-octylphenyl)pentanoic acid Drug Info [530721]
4-amino-6-(4-octylphenyl)hexanoic acid Drug Info [530721]
GNF-PF-78 Drug Info [531262]
GNF-PF-826 Drug Info [531262]
NOX-S91 Drug Info [543701]
Sphingosine-1-phosphate Drug Info [530799]
[3-(4-Nonyl-benzylamino)-propyl]-phosphonic acid Drug Info [527193]
Modulator ACT-128800 Drug Info [543701]
ASP-4058 Drug Info [533005]
BAF312 Drug Info [532456]
CS-0777 Drug Info [531862], [532807]
Fingolimod Drug Info [531351], [536837]
KRP-107 Drug Info [543701]
MT-1303 Drug Info [533299]
NIBR-785 Drug Info [543701]
Agonist AFD(R) Drug Info [526319]
AUY954 Drug Info [528529]
BMS-520 Drug Info [543701]
compound 26 Drug Info [527767]
CYM5181 Drug Info [529645]
CYM5442 Drug Info [529645]
FTY720-phosphate Drug Info [526319]
GSK-1842799C Drug Info [543701]
GSK-2018682 Drug Info [532456]
KRP 203-phosphate Drug Info [529067]
KRP-203 Drug Info [532341], [532456]
LPA Drug Info [534686]
ONO-4641 Drug Info [532134], [532456]
PF-4629991 Drug Info [551919]
RPC-1063 Drug Info [532456]
SEW2871 Drug Info [526934]
Sphingosine-1-phosphate receptor-1 agonist Drug Info [551792]
Antagonist AMG-247 Drug Info [543701]
NIBR-0213 Drug Info [532051]
VPC03090-P Drug Info [531499]
VPC23019 Drug Info [527334]
VPC44116 Drug Info [528528]
W146 Drug Info [528303]
XL-541 Drug Info [531753]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway FoxO signaling pathway
Sphingolipid signaling pathway
Neuroactive ligand-receptor interaction
NetPath Pathway IL4 Signaling Pathway
TGF_beta_Receptor Signaling Pathway
IL2 Signaling Pathway
Pathway Interaction Database Fc-epsilon receptor I signaling in mast cells
S1P3 pathway
S1P1 pathway
Sphingosine 1-phosphate (S1P) pathway
PDGFR-beta signaling pathway
Reactome G alpha (i) signalling events
Lysosphingolipid and LPA receptors
WikiPathways Signal Transduction of S1P Receptor
Small Ligand GPCRs
GPCR ligand binding
GPCR downstream signaling
GPCRs, Other
References
Ref 522226ClinicalTrials.gov (NCT00616733) 12-week Safety Evaluation of Oral CS-0777 in Multiple Sclerosis Patients. U.S. National Institutes of Health.
Ref 522296ClinicalTrials.gov (NCT00661414) Safety Study of ASONEP (Sonepcizumab/LT1009) to Treat Advanced Solid Tumors. U.S. National Institutes of Health.
Ref 522598ClinicalTrials.gov (NCT00852670) ACT-128800 in Psoriasis. U.S. National Institutes of Health.
Ref 523225ClinicalTrials.gov (NCT01226745) A Safety and Efficacy Extension Study of ONO-4641 (MSC2430913A) in Patients With Relapsing-Remitting Multiple Sclerosis. U.S. National Institutes of Health.
Ref 523356ClinicalTrials.gov (NCT01294774) Safety and Efficacy of KRP203 in Subacute Cutaneous Lupus Erythematosus. U.S. National Institutes of Health.
Ref 523536ClinicalTrials.gov (NCT01387217) GSK2018682 FTIH in Healthy Volunteers. U.S. National Institutes of Health.
Ref 523681ClinicalTrials.gov (NCT01466322) A Study to Assess the Relative Bioavailability of Different Formulations of GSK2018682, a Sphingosine-1-phosphate Receptor Subtype 1 Agonist, in Healthy Volunteers.. U.S. National Institutes of Health.
Ref 524022ClinicalTrials.gov (NCT01665144) Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). U.S. National Institutes of Health.
Ref 524345ClinicalTrials.gov (NCT01890655) Extension Study of MT-1303. U.S. National Institutes of Health.
Ref 525004ClinicalTrials.gov (NCT02294058) Phase 3 Study of RPC1063 in Relapsing MS. U.S. National Institutes of Health.
Ref 531351Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
Ref 533005ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS One. 2014 Oct 27;9(10):e110819.
Ref 539536(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2407).
Ref 543301(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 911).
Ref 548837Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029368)
Ref 548892Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030004)
Ref 551791Clinical pipeline report, company report or official report of Actelion.
Ref 526319The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002 Jun 14;277(24):21453-7. Epub 2002 Apr 19.
Ref 526934Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem. 2004 Apr 2;279(14):13839-48. Epub 2004 Jan 19.
Ref 527193Bioorg Med Chem Lett. 2004 Oct 4;14(19):4861-6.Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors.
Ref 527334Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem. 2005 Mar 18;280(11):9833-41. Epub 2004 Dec 8.
Ref 527349J Med Chem. 2004 Dec 30;47(27):6662-5.A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists.
Ref 527767Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3. J Med Chem. 2005 Oct 6;48(20):6169-73.
Ref 528303Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol. 2006 Aug;2(8):434-41. Epub 2006 Jul 9.
Ref 528528Synthesis and biological evaluation of gamma-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg Med Chem. 2007 Jan 15;15(2):663-77. Epub2006 Nov 1.
Ref 528529A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol. 2006 Nov;13(11):1227-34.
Ref 529067A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice. J Pharmacol Exp Ther. 2008 Jan;324(1):276-83. Epub 2007 Sep 26.
Ref 529645Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions. Mol Pharmacol. 2008 Nov;74(5):1308-18.
Ref 530125Nat Chem Biol. 2009 Jun;5(6):428-34.Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors.
Ref 530721Bioorg Med Chem Lett. 2010 Mar 1;20(5):1485-7. Epub 2010 Jan 28.S1P receptor mediated activity of FTY720 phosphate mimics.
Ref 530799Bioorg Med Chem Lett. 2010 Apr 15;20(8):2520-4. Epub 2010 Mar 3.Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists.
Ref 531262Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6. Epub 2010 Oct 21.In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2).
Ref 531351Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
Ref 531499Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther. 2011 Sep;338(3):879-89.
Ref 531633Prevention of ocular scarring after glaucoma filtering surgery using the monoclonal antibody LT1009 (Sonepcizumab) in a rabbit model. J Glaucoma. 2013 Feb;22(2):145-51.
Ref 531753Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists. J Med Chem. 2012 Feb 9;55(3):1368-81.
Ref 531862Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients. J Neuroimmunol. 2012 May 15;246(1-2):100-7.
Ref 532051A potent and selective S1P(1) antagonist with efficacy in experimental autoimmune encephalomyelitis. Chem Biol. 2012 Sep 21;19(9):1142-51.
Ref 532134Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis. Clin Exp Immunol. 2013 Jan;171(1):54-62.
Ref 532341KRP-203, sphingosine 1-phosphate receptor type 1 agonist, ameliorates atherosclerosis in LDL-R-/- mice. Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1505-12.
Ref 532456Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013 Sep;12(9):688-702.
Ref 532807Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist. ACS Med Chem Lett. 2011 Mar 2;2(5):368-72.
Ref 533005ASP4058, a novel agonist for sphingosine 1-phosphate receptors 1 and 5, ameliorates rodent experimental autoimmune encephalomyelitis with a favorable safety profile. PLoS One. 2014 Oct 27;9(10):e110819.
Ref 533299Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis. CNS Drugs. 2015 Jul;29(7):565-75.
Ref 534686Lysophosphatidic acid stimulates the G-protein-coupled receptor EDG-1 as a low affinity agonist. J Biol Chem. 1998 Aug 21;273(34):22105-12.
Ref 536837Emerging oral drugs for multiple sclerosis. Expert Opin Emerg Drugs. 2008 Sep;13(3):465-77.
Ref 543701(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 275).
Ref 550421National Cancer Institute Drug Dictionary (drug id 595163).
Ref 551792Clinical pipeline report, company report or official report of Actelion.
Ref 551919US patent application no. 2010,0158,905, Combination therapy of arthritis with tranilast.

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