Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9JZCK)

• DTT Name: Sphingosine-1-phosphate receptor 1 (S1PR1)
• Synonyms: Sphingosine 1-phosphate receptor Edg-1; S1P1; S1P receptor Edg-1; S1P receptor 1; Endothelial differentiation G-protein coupled receptor 1; CHEDG1; CD363
• Gene Name: S1PR1
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: S1PR1_HUMAN
• TTD ID: T13852
• Sequence:
  MGPTSVPLVKAHRSSVSDYVNYDIIVRHYNYTGKLNISADKENSIKLTSVVFILICCFII
  LENIFVLLTIWKTKKFHRPMYYFIGNLALSDLLAGVAYTANLLLSGATTYKLTPAQWFLR
  EGSMFVALSASVFSLLAIAIERYITMLKMKLHNGSNNFRLFLLISACWVISLILGGLPIM
  GWNCISALSSCSTVLPLYHKHYILFCTTVFTLLLLSIVILYCRIYSLVRTRSRRLTFRKN
  ISKASRSSEKSLALLKTVIIVLSVFIACWAPLFILLLLDVGCKVKTCDILFRAEYFLVLA
  VLNSGTNPIIYTLTNKEMRRAFIRIMSCCKCPSGDSAGKFKRPIIAGMEFSRSKSDNSSH
  PQKDEGDNPETIMSSGNVNSSS
• Function: Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP 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 and bone homeostasis. 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. G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Lysosphingolipid and LPA receptors (R-HSA-419408)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Etrasimod	DMT0A3Y	Ulcerative colitis	DD71	Approved	[2]
Fingolimod	DM5JVAN	Multiple sclerosis	8A40	Approved	[1]
Ozanimod	DMT6AM2	Multiple sclerosis	8A40	Approved	[3]
Ponesimod	DMEAOYJ	Multiple sclerosis	8A40	Approved	[4]
Siponimod	DM2R86O	Multiple sclerosis	8A40	Approved	[5]

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CBP-307	DM3TH6Y	Ulcerative colitis	DD71	Phase 2	[6]
KRP-203	DMOW9X2	Cutaneous lupus erythematosus	EB5Z	Phase 2	[7]
MT-1303	DMSE9TH	Crohn disease	DD70	Phase 2	[8]
ONO-4641	DMLUM3Y	Rheumatoid arthritis	FA20	Phase 2	[7]
VTX-002	DMZ8Z5A	Ulcerative colitis	DD71	Phase 2	[9]
ASP-4058	DM1RD0T	Multiple sclerosis	8A40	Phase 1	[10]
BMS-986104	DMZ4WMT	Rheumatoid arthritis	FA20	Phase 1	[2]
CS-0777	DMG0SPO	Multiple sclerosis	8A40	Phase 1	[11]
GSK-2018682	DMRU4YV	Immune System disease	4A01-4B41	Phase 1	[7]
SAR247799	DMUAJZD	Cardiovascular disease	BA00-BE2Z	Phase 1	[12]
Sonepcizumab	DMB3YZJ	Macular degeneration	9B78.3	Phase 1	[7]
Sphingosine-1-phosphate	DMJCQKA	Acne vulgaris	ED80	Phase 1	[13]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-4629991	DMNLAU7	Rheumatoid arthritis	FA20	Discontinued in Phase 1	[14]
XL-541	DM965P4	Solid tumour/cancer	2A00-2F9Z	Terminated	[15]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(3-Tetradecylamino-cyclohexyl)-phosphonic acid	DM6P35D	Discovery agent	N.A.	Investigative	[16]
(3-Tetradecylamino-cyclopentyl)-phosphonic acid	DMFMBPT	Discovery agent	N.A.	Investigative	[16]
(S)-FTY720P	DM5WETL	N. A.	N. A.	Investigative	[17]
1-(4-nonylbenzyl)azetidine-3-carboxylic acid	DMQKMCG	Discovery agent	N.A.	Investigative	[18]
1-(4-nonylbenzyl)pyrrolidin-3-ylphosphonic acid	DM8U2HP	Discovery agent	N.A.	Investigative	[18]
1-(4-nonylbenzyl)pyrrolidine-3-carboxylic acid	DMAR39L	Discovery agent	N.A.	Investigative	[18]
3-(N-alkylamino) propylphosphonic acid derivative	DMJDG9C	Discovery agent	N.A.	Investigative	[16]
3-(tetradecylamino)propylphosphonic acid	DMNA6LF	Discovery agent	N.A.	Investigative	[18]
3-amino-5-(4-octylphenyl)pentanoic acid	DMONHFR	Discovery agent	N.A.	Investigative	[19]
4-amino-6-(4-octylphenyl)hexanoic acid	DMZRM0Q	Discovery agent	N.A.	Investigative	[19]
AFD(R)	DME9Y8Q	Discovery agent	N.A.	Investigative	[20]
AMG-247	DMU6WR9	Inflammation	1A00-CA43.1	Investigative	[21]
AUY954	DMVGIO5	Discovery agent	N.A.	Investigative	[22]
BMS-520	DMAY9TM	Immune System disease	4A01-4B41	Investigative	[21]
CYM5181	DMGTZ9Q	Discovery agent	N.A.	Investigative	[23]
CYM5442	DMURD2E	Discovery agent	N.A.	Investigative	[23]
FTY720-phosphate	DMDZBQH	Discovery agent	N.A.	Investigative	[20]
GNF-PF-78	DM7SPRJ	Discovery agent	N.A.	Investigative	[24]
GNF-PF-826	DM37ORC	Discovery agent	N.A.	Investigative	[24]
GSK-1842799C	DM2KT17	Cardiovascular disease	BA00-BE2Z	Investigative	[21]
KRP 203-phosphate	DMLIK7X	Discovery agent	N.A.	Investigative	[25]
KRP-107	DM5KFBP	Autoimmune diabetes	5A10	Investigative	[21]
LPA	DMI5XR1	Discovery agent	N.A.	Investigative	[26]
NIBR-0213	DMH6MVJ	Discovery agent	N.A.	Investigative	[27]
NIBR-785	DMU0BMQ	Multiple sclerosis	8A40	Investigative	[21]
NOX-S91	DMVS6DW	Solid tumour/cancer	2A00-2F9Z	Investigative	[21]
SEW2871	DMJBW7X	Discovery agent	N.A.	Investigative	[28]
VPC03090-P	DMIXUM3	Discovery agent	N.A.	Investigative	[29]
VPC23019	DMVQFY4	Discovery agent	N.A.	Investigative	[30]
VPC44116	DMQ4OTJ	Discovery agent	N.A.	Investigative	[31]
W146	DMDYTSW	Discovery agent	N.A.	Investigative	[32]
[3-(4-Nonyl-benzylamino)-propyl]-phosphonic acid	DMGD487	Discovery agent	N.A.	Investigative	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	7.89E-08	-0.26	-0.5
Lung cancer	2C82	Lung tissue	1.41E-119	-2.24	-3.66
Rheumatoid arthritis	FA20	Synovial tissue	3.68E-03	-0.06	-0.15

References

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• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [6] Clinical pipeline report, company report or official report of Connect Biopharma
• [7] Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond. Nat Rev Drug Discov. 2013 Sep;12(9):688-702.
• [8] Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis. CNS Drugs. 2015 Jul;29(7):565-75.
• [9] Clinical pipeline report, company report or official report of Ventyx Biosciences
• [10] ASP4058, 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.
• [11] Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist. ACS Med Chem Lett. 2011 Mar 2;2(5):368-72.
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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• [14] US patent application no. 2010,0158,905, Combination therapy of arthritis with tranilast.
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• [24] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [25] A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-d... J Pharmacol Exp Ther. 2008 Jan;324(1):276-83.
• [26] Lysophosphatidic acid stimulates the G-protein-coupled receptor EDG-1 as a low affinity agonist. J Biol Chem. 1998 Aug 21;273(34):22105-12.
• [27] A potent and selective S1P(1) antagonist with efficacy in experimental autoimmune encephalomyelitis. Chem Biol. 2012 Sep 21;19(9):1142-51.
• [28] Sphingosine 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.
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