S1PR2

Summary

S1PR2 (sphingosine-1-phosphate receptor 2, HGNC:3169) is a protein-coding gene on chromosome 19p13.2, encoding Sphingosine 1-phosphate receptor 2 (O95136). Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P).

This gene encodes a member of the G protein-coupled receptors, as well as the EDG family of proteins. The encoded protein is a receptor for sphingosine 1-phosphate, which participates in cell proliferation, survival, and transcriptional activation. Defects in this gene have been associated with congenital profound deafness.

Source: NCBI Gene 9294 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Strong, ClinGen) — +2 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 144 total — 2 pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004230

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3169
Approved symbol	S1PR2
Name	sphingosine-1-phosphate receptor 2
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	Gpcr13, H218, AGR16
Ensembl gene	ENSG00000267534
Ensembl biotype	protein_coding
OMIM	605111
Entrez	9294

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000646641

RefSeq mRNA: 1 — MANE Select: NM_004230 NM_004230

CCDS: CCDS12229

Canonical transcript exons

ENST00000646641 — 2 exons

Exon	Start	End
ENSE00001237868	10221433	10224947
ENSE00003827265	10231204	10231331

Expression profiles

Bgee: expression breadth ubiquitous, 211 present calls, max score 87.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.7441 / max 106.6699, expressed in 1650 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179095	9.7441	1650

Top tissues by expression

242 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	87.58	gold quality
epithelial cell of pancreas	CL:0000083	87.13	silver quality
heart right ventricle	UBERON:0002080	86.91	silver quality
cardiac muscle of right atrium	UBERON:0003379	85.26	gold quality
vena cava	UBERON:0004087	85.12	silver quality
stromal cell of endometrium	CL:0002255	84.66	gold quality
parotid gland	UBERON:0001831	83.91	silver quality
placenta	UBERON:0001987	83.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.72	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.86	gold quality
upper lobe of left lung	UBERON:0008952	81.36	gold quality
upper lobe of lung	UBERON:0008948	80.97	gold quality
pancreatic ductal cell	CL:0002079	80.96	silver quality
sperm	CL:0000019	80.91	silver quality
left uterine tube	UBERON:0001303	80.55	gold quality
mucosa of stomach	UBERON:0001199	80.42	gold quality
endocervix	UBERON:0000458	79.98	gold quality
buccal mucosa cell	CL:0002336	79.80	gold quality
visceral pleura	UBERON:0002401	79.72	gold quality
trachea	UBERON:0003126	79.15	gold quality
pericardium	UBERON:0002407	79.11	silver quality
deltoid	UBERON:0001476	78.49	silver quality
left testis	UBERON:0004533	78.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.36	silver quality
lung	UBERON:0002048	78.34	gold quality
lateral nuclear group of thalamus	UBERON:0002736	78.31	gold quality
right testis	UBERON:0004534	78.30	gold quality
right lung	UBERON:0002167	78.17	gold quality
lymph node	UBERON:0000029	77.81	gold quality
tongue	UBERON:0001723	77.43	silver quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	20.48
E-MTAB-7051	no	2855.68
E-MTAB-5061	no	3.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

123 targeting S1PR2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4728-5P	99.85	69.39	4718

Literature-anchored findings (GeneRIF, showing 40)

• suppress rac protein, a Rho family G protein and cell motility (PMID:11915348)
• Amyloid beta-protein stimulated in monocytes the gene expression for sphingosine-1-phosphate receptor 5, which is amyloid beta-protein-induced migration. (PMID:15208267)
• S1P2R receptor actively regulates the PTEN phosphatase by a Rho GTPase-dependent pathway to inhibit cell migration. (PMID:15764699)
• S1P2R activation in endothelial cells increases vascular permeability. The balance of S1P1 and S1P2 receptors in the endothelium may determine the regulation of vascular permeability by S1P. (PMID:17431187)
• antagonism of the S1P2R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization (PMID:17710232)
• These results suggest that S1P(2) receptors/G(12/13)-proteins/Rho signaling pathways mediate S1P-induced inhibition of glioma cell migration. (PMID:18088600)
• Results suggest that S1PR2 is involved in COX2 dependent effects of high-density lipoprotein on vascular smooth muscle. (PMID:18612546)
• Plays essential roles in the pathogenesis of rheumatoid arthritis by modulating fibroblast-like synoviocytes migration, cytokine/chemokine production, and cell survival. (PMID:18658144)
• impairment of function in senescent ECs in culture is mediated by an increase in S1P signaling through S1P(2)-mediated activation of the lipid phosphatase PTEN (PMID:18765664)
• These data suggest that CTGF protein induced by S1P2 might act as a growth inhibitor in Wilms’ tumor. (PMID:18922980)
• the S1P(2) receptor is involved in S1P-induced platelet aggregation and Rho kinase activation. (PMID:19139947)
• S1P(2) signaling may play a critical role in suppressing diffuse large B-cell lymphoma (PMID:19903857)
• S1PR2 receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release (PMID:20194630)
• SphK/S1P/S1PRs signaling axis plays an important role in liver fibrosis and is involved in the directed migration of hepatic myofibroblasts into the damaged areas. (PMID:21145832)
• S1P2, and not S1P1 or S1P3, receptor activation increases conventional outflow resistance in whole-eye perfusions. (PMID:21289286)
• Inflammatory mediators lipopolysaccharide and TNF-alpha induce S1PR2 expression in endothelium, suggesting that S1PR2 up-regulation may be involved in LPS and TNF-alpha elicited endothelial barrier dysfunction. (PMID:22244964)
• abdominal aortic aneurysms have down-regulation of the S1P2 protein with simultaneous up-regulation of the S1P3 protein, but not S1P1 (PMID:22547907)
• S1P receptors S1P1,2,3 are expressed in human anaplastic thyroid cancer C643 and THJ-16T cells at both mRNA and protein levels (PMID:22889737)
• identify the S1PR2 as the specific and necessary receptor to induce phosphorylation of ERM proteins and subsequent filopodia formation (PMID:23106337)
• Sphingosine 1-phosphate (S1P) receptors 1 and 2 coordinately induce mesenchymal cell migration through S1P activation of complementary kinase pathways (PMID:23300082)
• S1PR agonists are pro-fibrotic via S1P2R and S1P3R stimulation using Smad-independent pathways. (PMID:23589284)
• Data indicate that EGF-induced cellular invasion required sphingosine-1-phosphate (S1P)-mediated activation of sphingosine-1-phosphate 2 receptor (S1PR2) and ezrin phosphorylation. (PMID:23629860)
• Activation of the S1P2 receptor counteracts the detrimental phosphorylation of p38 MAPK by IL-1beta. (PMID:23666803)
• S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium. (PMID:23723450)
• TNFalpha treatment activates autocrine S1P/S1P2 signaling, which subsequently activates NFkappaB and leads to the proinflammatory responses in endothelial cell (PMID:23770055)
• The S1P2R specifically activates RhoC via G12/13 proteins and LARG. (PMID:23993968)
• we provide evidences that S1PR1/3, but not S1PR2, negatively regulate the expression of collagen in hMSCs using cellular and molecular approaches (PMID:24038457)
• extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. (PMID:24064301)
• Sphingosylphosphorylcholine stimulates alpha-SMA protein expression and human lung fibroblast mediated collagen gel contraction via S1P2 receptor. (PMID:24614064)
• Conjugated bile acids promote cholangiocarcinoma growth through S1PR2. (PMID:24700501)
• S1PR2 expression was increased in disease-susceptible regions of the CNS of female patients with multiple sclerosis compared with their male counterparts. (PMID:24812668)
• Data indicate that sphingosine 1-phosphate (S1P) and hepatocyte growth factor (HGF) induced transloaction of integrin beta4, S1P receptors S1PR2 and S1PR3 to endothelial cell membrane caveolin-enriched microdomains (CEMs). (PMID:24851274)
• Data show that sphingosine kinase SphK1 and sphingosine-1-phosphate (S1P) receptors S1P1, S1P2, S1P3, and S1P5 were expressed from primary, up to recurrent and secondary glioblastomas, with sphingosine kinase SphK2 levels were highest in primary tumors. (PMID:24903384)
• Activation of S1PR2-calcium influx-RhoA/ROCK dominates the high-dose S1P-induced endothelial monolayer hyperpermeability response. (PMID:25557733)
• both S1PR1 and S1PR2 play a pivotal role in hyperglycemia-induced EC dysfunction and endothelial injury by reducing and enhancing the production of oxidative stress. (PMID:25673082)
• AB1 displayed potency at least equivalent to JTE-013 in affecting signaling molecules downstream of S1P2. (PMID:26105954)
• be detected in the human cerebrovascular endothelium (PMID:26243335)
• Sphingosine 1-phosphate-induced IL-8 gene expression is mainly regulated via S1PR(1), and its secretion is regulated through S1PR(2) receptor subtype. (PMID:26321412)
• S1PR2 plays a critical role in TCA-induced COX-2 expression and CCA growth and may represent a novel therapeutic target for CCA. (PMID:26518876)
• S1PR2 mediates Rho activation in normal cells neighboring RasV12-transformed cells. (PMID:26631556)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	s1pr2	ENSDARG00000036548
mus_musculus	S1pr2	ENSMUSG00000043895
rattus_norvegicus	S1pr2	ENSRNOG00000020653

Paralogs (18): LPAR2 (ENSG00000064547), CNR1 (ENSG00000118432), MC3R (ENSG00000124089), S1PR4 (ENSG00000125910), GPR12 (ENSG00000132975), GPR6 (ENSG00000146360), GPR119 (ENSG00000147262), MC4R (ENSG00000166603), S1PR1 (ENSG00000170989), LPAR3 (ENSG00000171517), MC5R (ENSG00000176136), S1PR5 (ENSG00000180739), GPR3 (ENSG00000181773), MC2R (ENSG00000185231), CNR2 (ENSG00000188822), LPAR1 (ENSG00000198121), S1PR3 (ENSG00000213694), MC1R (ENSG00000258839)

Protein

Protein identifiers

Sphingosine 1-phosphate receptor 2 — O95136 (reviewed: O95136)

Alternative names: Endothelial differentiation G-protein coupled receptor 5, Sphingosine 1-phosphate receptor Edg-5

All UniProt accessions (1): O95136

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effects 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. Receptor for the chemokine-like protein FAM19A5. Mediates the inhibitory effect of FAM19A5 on vascular smooth muscle cell proliferation and migration. In lymphoid follicles, couples the binding of S1P to the activation of GNA13 and downstream inhibition of AKT activation leading to suppression of germinal center (GC) B cell growth and migration outside the GC niche.

Subcellular location. Cell membrane.

Disease relevance. Deafness, autosomal recessive, 68 (DFNB68) [MIM:610419] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_004221* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR004061	S1P_rcpt	Family
IPR004063	EDG5_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (46 total): helix 12, topological domain 8, mutagenesis site 8, transmembrane region 7, sequence variant 2, sequence conflict 2, turn 2, strand 2, chain 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7T6B	ELECTRON MICROSCOPY	3.19
9W0M	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95136-F1	82.73	0.56

Antibody-complex structures (SAbDab): 1 — 7T6B

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 305

Glycosylation sites (1): 19

Mutagenesis-validated functional residues (8):

Position	Phenotype
147	no effect on protein expression at the cell surface. decreases s1pr2-mediated inhibition of akt activation and b cell mi
156	loss of protein expression.
194	loss of protein expression.
245	markedly decreases protein expression.
248	loss of protein expression.
256	loss of protein expression.
272	decreases protein expression. no effect on s1p-mediated inhibition of akt signaling, gc b cell growth and migration.
329	no effect on protein expression or s1pr2-mediated inhibition of akt activation and b cell migration.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-418594	G alpha (i) signalling events
R-HSA-419408	Lysosphingolipid and LPA receptors
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 215 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, CREL_01, GOBP_EPITHELIUM_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_SYNAPSE_ASSEMBLY, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_SPHINGOLIPID_MEDIATED_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, AAAYRNCTG_UNKNOWN, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION

GO Biological Process (11): sphingosine-1-phosphate receptor signaling pathway (GO:0003376), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), positive regulation of cell population proliferation (GO:0008284), actin cytoskeleton organization (GO:0030036), filopodium assembly (GO:0046847), excitatory postsynaptic potential (GO:0060079), negative regulation of excitatory postsynaptic potential (GO:0090394), regulation of postsynapse assembly (GO:0150052), positive regulation of establishment of endothelial barrier (GO:1903142), signal transduction (GO:0007165)

GO Molecular Function (7): G protein-coupled receptor binding (GO:0001664), G protein-coupled receptor activity (GO:0004930), integrin binding (GO:0005178), lipid binding (GO:0008289), G protein-coupled peptide receptor activity (GO:0008528), sphingosine-1-phosphate receptor activity (GO:0038036), protein binding (GO:0005515)

GO Cellular Component (6): cytoplasm (GO:0005737), plasma membrane (GO:0005886), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Class A/1 (Rhodopsin-like receptors)	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
synapse	3
G protein-coupled receptor signaling pathway	2
G protein-coupled receptor activity	2
signaling receptor binding	2
binding	2
sphingolipid mediated signaling pathway	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cytoskeleton organization	1
actin filament-based process	1
plasma membrane bounded cell projection assembly	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
negative regulation of biological process	1
excitatory postsynaptic potential	1
modulation of excitatory postsynaptic potential	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
establishment of endothelial barrier	1
positive regulation of endothelial cell development	1
regulation of establishment of endothelial barrier	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
protein-containing complex binding	1
cell adhesion molecule binding	1
peptide receptor activity	1
sphingosine-1-phosphate receptor signaling pathway	1
bioactive lipid receptor activity	1
intracellular anatomical structure	1
membrane	1

Protein interactions and networks

STRING

1066 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
S1PR2	GNAQ	P50148	985
S1PR2	SPHK1	Q9NYA1	956
S1PR2	GNA13	Q14344	930
S1PR2	GNA12	Q03113	919
S1PR2	SPHK2	Q9NRA0	890
S1PR2	APOM	O95445	853
S1PR2	SPNS2	Q8IVW8	796
S1PR2	GPBAR1	Q8TDU6	754
S1PR2	SGPL1	O95470	738
S1PR2	RHOA	P06749	706
S1PR2	RTN4	Q9NQC3	705
S1PR2	MFSD2B	A6NFX1	691
S1PR2	CERS6	Q6ZMG9	614
S1PR2	CERS2	Q96G23	606
S1PR2	ARHGEF12	Q9NZN5	586

IntAct

16 interactions, top by confidence:

A	B	Type	Score
Rtn4	S1PR2	psi-mi:“MI:0915”(physical association)	0.530
Rtn4	S1PR2	psi-mi:“MI:0407”(direct interaction)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
S1PR2	PALM3	psi-mi:“MI:0914”(association)	0.530
S1PR2	ITGB4	psi-mi:“MI:0915”(physical association)	0.400
TRADD	HNRNPCL2	psi-mi:“MI:0914”(association)	0.350
FADD	CHUK	psi-mi:“MI:0914”(association)	0.350
SHARPIN	UMAD1	psi-mi:“MI:0914”(association)	0.350
TNFAIP3	FZD7	psi-mi:“MI:0914”(association)	0.350
TTYH1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TSPAN15	TMEM223	psi-mi:“MI:0914”(association)	0.350
TNFSF18	TMEM120B	psi-mi:“MI:0914”(association)	0.350
S1PR1	S1PR2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (44): S1PR2 (Affinity Capture-MS), C8G (Affinity Capture-MS), NDRG1 (Affinity Capture-MS), FKBP14 (Affinity Capture-MS), PALM3 (Affinity Capture-MS), SRC (Affinity Capture-MS), HPCAL1 (Affinity Capture-MS), ARL6IP5 (Affinity Capture-MS), WDFY1 (Affinity Capture-MS), LGALS1 (Affinity Capture-MS), CSNK1G3 (Affinity Capture-MS), PTER (Affinity Capture-MS), S1PR2 (Affinity Capture-MS), REEP6 (Affinity Capture-MS), ATP5B (Affinity Capture-MS)

ESM2 similar proteins: A5D7K8, O35932, O95136, O95977, P21731, P30557, P30987, P34972, P34978, P34979, P34980, P35375, P35408, P37289, P43088, P43114, P43115, P43116, P43117, P43118, P43119, P43252, P43253, P46069, P47752, P47901, P47936, P50131, P52592, P56486, P70263, P70597, P79393, Q13258, Q28691, Q28905, Q5R949, Q62053, Q62928, Q8MJ08

Diamond homologs: O02777, O08530, O77408, O77621, O95136, P20272, P21453, P21554, P30546, P30966, P31389, P31390, P34972, P35367, P47746, P47752, P47936, P48303, P52592, P56971, P70174, Q17232, Q28928, Q333S9, Q5E9P3, Q5IS73, Q71SP5, Q7JQF1, Q801M1, Q90WY5, Q98894, Q98895, Q9DDK4, Q9H228, Q9I8K8, Q9N2B0, Q9N2B1, Q9N2B2, Q9PUI7, Q9PUQ8

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
“sphingosine 1-phosphate”	up-regulates	S1PR2	“chemical activation”
S1PR2	up-regulates	GNA12	binding
S1PR2	up-regulates	GNA13	binding
S1PR2	“up-regulates activity”	GNAI1	binding
S1PR2	“up-regulates activity”	GNAI3	binding
S1PR2	“up-regulates activity”	GNAO1	binding
S1PR2	“up-regulates activity”	GNAZ	binding
S1PR2	“up-regulates activity”	GNAQ	binding
S1PR2	“up-regulates activity”	GNA14	binding
S1PR2	“up-regulates activity”	GNA12	binding
S1PR2	“up-regulates activity”	GNA13	binding
“sphingosine 1-phosphate(1-)”	“up-regulates activity”	S1PR2	“chemical activation”
S1PR2	up-regulates	GNAI1	binding
S1PR2	up-regulates	GNAQ	binding
“sphingosine 1-phosphate”	“up-regulates activity”	S1PR2	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of TNFR1 signaling	5	86.1×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	5	24.2×	3e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

144 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	69
Likely benign	47
Benign	11

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
219249	NM_004230.4(S1PR2):c.419A>G (p.Tyr140Cys)	Pathogenic
219259	NM_004230.4(S1PR2):c.323G>C (p.Arg108Pro)	Pathogenic

SpliceAI

491 predictions. Top by Δscore:

Variant	Effect	Δscore
19:10224948:C:CC	acceptor_gain	1.0000
19:10224943:CAGAA:C	acceptor_gain	0.9900
19:10224944:AGAA:A	acceptor_gain	0.9900
19:10224945:GAA:G	acceptor_gain	0.9900
19:10224946:AAC:A	acceptor_loss	0.9900
19:10224948:CTGCA:C	acceptor_loss	0.9900
19:10224949:T:G	acceptor_loss	0.9900
19:10230913:T:TA	donor_gain	0.9900
19:10231199:CTCA:C	donor_loss	0.9900
19:10231200:TCAC:T	donor_loss	0.9900
19:10231201:CA:C	donor_loss	0.9900
19:10231202:A:C	donor_loss	0.9900
19:10224946:AA:A	acceptor_gain	0.9800
19:10224951:C:CT	acceptor_gain	0.9800
19:10230921:C:A	donor_gain	0.9800
19:10224952:A:T	acceptor_gain	0.9700
19:10230920:T:TA	donor_gain	0.9700
19:10231198:GCTCA:G	donor_loss	0.9700
19:10231203:CCTGG:C	donor_gain	0.9700
19:10224960:C:CT	acceptor_gain	0.9600
19:10230211:T:C	donor_gain	0.9600
19:10230975:T:TA	donor_gain	0.9600
19:10224947:ACTG:A	acceptor_gain	0.9500
19:10224948:CTGC:C	acceptor_gain	0.9500
19:10230884:C:CA	donor_gain	0.9400
19:10230885:C:A	donor_gain	0.9400
19:10230931:C:CA	donor_gain	0.9400
19:10224946:AACT:A	acceptor_gain	0.9200
19:10231202:A:AC	donor_gain	0.9200
19:10231203:C:CC	donor_gain	0.9200

AlphaMissense

2245 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:10224540:G:C	S122R	0.999
19:10224540:G:T	S122R	0.999
19:10224542:T:G	S122R	0.999
19:10224670:T:A	D79V	0.999
19:10224670:T:G	D79A	0.999
19:10224367:G:A	S180F	0.998
19:10224390:G:C	C172W	0.998
19:10224440:A:G	W156R	0.998
19:10224440:A:T	W156R	0.998
19:10224669:A:C	D79E	0.998
19:10224669:A:T	D79E	0.998
19:10224670:T:C	D79G	0.998
19:10224684:G:C	N74K	0.998
19:10224684:G:T	N74K	0.998
19:10224753:G:C	N51K	0.998
19:10224753:G:T	N51K	0.998
19:10224170:A:G	W246R	0.997
19:10224170:A:T	W246R	0.997
19:10224180:A:C	F242L	0.997
19:10224180:A:T	F242L	0.997
19:10224182:A:G	F242L	0.997
19:10224369:G:C	C179W	0.997
19:10224370:C:T	C179Y	0.997
19:10224659:C:G	G83R	0.997
19:10224754:T:A	N51I	0.997
19:10224754:T:G	N51T	0.997
19:10224755:T:A	N51Y	0.997
19:10224173:A:G	C245R	0.996
19:10224188:C:G	G240R	0.996
19:10224370:C:G	C179S	0.996

dbSNP variants (sampled 300 via entrez): RS1001005824 (19:10229566 A>G), RS1001021154 (19:10231882 A>T), RS1001314264 (19:10226594 C>T), RS1001344760 (19:10226938 C>A,T), RS1001437376 (19:10231822 A>G,T), RS1001451445 (19:10225243 G>A), RS1001503098 (19:10221136 A>G), RS1001587339 (19:10231549 C>A,G,T), RS1001788265 (19:10226588 C>G,T), RS1001965869 (19:10221823 CACAT>C), RS1002240112 (19:10222190 G>A), RS1002354863 (19:10226345 A>G), RS1002966608 (19:10231756 T>G), RS1003080693 (19:10231442 C>G,T), RS1003305087 (19:10233072 C>T)

Disease associations

OMIM: gene MIM:605111 | disease phenotypes: MIM:610419

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Strong	Unknown
autosomal recessive nonsyndromic hearing loss 68	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Strong	AR

Mondo (3): autosomal recessive nonsyndromic hearing loss 68 (MONDO:0012485), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (1): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0003593	Infantile onset

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST004611_146	High light scatter reticulocyte count	4.000000e-09
GCST004612_93	High light scatter reticulocyte percentage of red cells	2.000000e-09
GCST004619_134	Reticulocyte fraction of red cells	3.000000e-23
GCST004622_71	Reticulocyte count	7.000000e-26
GCST004628_109	Immature fraction of reticulocytes	1.000000e-15
GCST005998_25	Alanine transaminase levels	2.000000e-08
GCST007267_152	Systolic blood pressure	7.000000e-10
GCST011352_8	Alanine aminotransferase levels	2.000000e-10
GCST90002385_312	High light scatter reticulocyte count	6.000000e-11
GCST90002385_313	High light scatter reticulocyte count	2.000000e-20
GCST90002386_61	High light scatter reticulocyte percentage of red cells	4.000000e-10
GCST90002386_62	High light scatter reticulocyte percentage of red cells	9.000000e-21
GCST90002387_40	Immature fraction of reticulocytes	1.000000e-12
GCST90002405_580	Reticulocyte count	3.000000e-10
GCST90002405_581	Reticulocyte count	1.000000e-18
GCST90002406_482	Reticulocyte fraction of red cells	5.000000e-09
GCST90002406_483	Reticulocyte fraction of red cells	4.000000e-20
GCST90002407_358	White blood cell count	5.000000e-09
GCST90011898_62	Alanine aminotransferase levels	1.000000e-16
GCST90011900_159	Serum alkaline phosphatase levels	2.000000e-08
GCST90013405_102	Liver enzyme levels (alanine transaminase)	3.000000e-20
GCST90013406_205	Liver enzyme levels (alkaline phosphatase)	2.000000e-23
GCST90013407_118	Liver enzyme levels (gamma-glutamyl transferase)	3.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0006335	systolic blood pressure
EFO:0004533	alkaline phosphatase measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)
C563669	Deafness, Autosomal Recessive 68 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363041 (PROTEIN FAMILY), CHEMBL2955 (SINGLE PROTEIN), CHEMBL3430884 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,588 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3707247	OZANIMOD	4	1,588

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Lysophospholipid (S1P) receptors

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
compound 16 [PMID: 26794040]	Antagonist	8.09	pIC50
JTE-013	Antagonist	7.77	pIC50
sphingosine 1-phosphate	Agonist	7.69	pKd
fingolimod-phosphate	Agonist	7.46	pEC50
CYM-5478	Agonist	6.92	pEC50
CYM5520	Agonist	6.32	pEC50
AUY954	Agonist	5.0	pEC50
ozanimod	Agonist	5.0	pEC50
compound 43 [PMID: 26751273]	Agonist	4.5	pEC50

Binding affinities (BindingDB)

113 measured of 181 human assays (181 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
{[(4Z)-2-amino-3-hydroxyoctadec-4-en-1-yl]oxy}phosphonic acid	KI	1.2 nM
1-(2,6-dichloro-4-pyridinyl)-3-[(3-methyl-4-propan-2-yl-1-prop-2-enylpyrazolo[5,4-b]pyridin-6-yl)amino]urea	IC50	1.2 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
[(2S)-2-amino-3-hydroxy-2-[2-(4-octylphenyl)ethyl]propoxy]phosphonic acid	KI	2.1 nM
2-[4-[3-(4-fluorophenoxy)-5-[[4-hydroxy-4-(2-methylpropyl)piperidine-1-carbonyl]amino]phenoxy]phenyl]-2-methylpropanoic acid	IC50	2.3 nM	US-8975409: Phenyl derivative
1-[4-[3-[[4-(2-ethylbutyl)-4-hydroxypiperidine-1-carbonyl]amino]-5-(4-fluorophenoxy)phenoxy]phenyl]cyclopropane-1-carboxylic acid	IC50	3 nM	US-8975409: Phenyl derivative
2-[4-[3-(4-fluorophenoxy)-5-[[4-hydroxy-4-(2-methylpropyl)piperidine-1-carbonyl]amino]benzoyl]oxyphenyl]-2-methylpropanoic acid	IC50	3.4 nM	US-8975409: Phenyl derivative
1-[2-chloro-6-(ethylamino)-4-pyridinyl]-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	4 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
{2-amino-3-hydroxy-2-[2-(4-octylphenyl)ethyl]propoxy}phosphonic acid	KI	4.1 nM
1-(2,6-dichloro-4-pyridinyl)-3-[[3-(3-hydroxypropyl)-1-methyl-7-propan-2-ylpyrazolo[4,5-b]pyridin-5-yl]amino]urea	IC50	5 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-[4-(3-hydroxypiperidine-1-carbonyl)phenoxy]phenyl]-4-hydroxypiperidine-1-carboxamide	IC50	5.1 nM	US-8975409: Phenyl derivative
4-[3-(4-fluorophenoxy)-5-[[4-(4-fluorophenyl)-4-hydroxypiperidine-1-carbonyl]amino]phenoxy]benzoic acid	IC50	6.2 nM	US-8975409: Phenyl derivative
4-(2-ethylbutyl)-N-[3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl]-4-hydroxypiperidine-1-carboxamide	IC50	7 nM	US-8975409: Phenyl derivative
1-(2,6-dichloro-4-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	7 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
2-[4-[3-(4-fluorophenoxy)-5-[[3-hydroxy-3-(2-methylpropyl)azetidine-1-carbonyl]amino]phenoxy]phenyl]-2-methylpropanoic acid	IC50	9.4 nM	US-8975409: Phenyl derivative
1-(2-chloro-6-propoxy-4-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	10 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
2-[[(2,6-dichloro-4-pyridinyl)carbamoylamino]-(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)amino]acetic acid	IC50	11 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-(2,6-dichloro-4-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)amino]urea	IC50	11 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-(2,6-dichloro-4-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(3-hydroxypropyl)amino]urea	IC50	19 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-[2-chloro-6-[ethyl(methyl)amino]-4-pyridinyl]-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	19 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-(2-chloro-6-ethoxy-4-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	29 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-(2,6-dichloro-4-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-prop-2-enylamino]urea	IC50	52 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-(2,6-dichloro-4-pyridinyl)-3-(3-methyl-4-propan-2-yl-1-prop-2-enylpyrazolo[5,4-b]pyridin-6-yl)oxyurea	IC50	52 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
1-(4,5-dichlorothiophen-2-yl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	64 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
N-[(S)-(5-bromo-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-3,4-dicyanobenzamide	IC50	99 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[2-(benzenecarboximidoylamino)-1-(3-chlorophenyl)-2-oxoethyl]-3,5-dichlorobenzamide	IC50	112 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[(S)-(5-bromo-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-3-chloro-4-cyanobenzamide	IC50	141 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
1-[2-chloro-6-(2-methoxyethoxy)-4-pyridinyl]-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	160 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
N-[(S)-(5-chloro-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-3-cyano-4-fluorobenzamide	IC50	197 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
4-bromo-N-[(S)-(5-chloro-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-3-methylbenzamide	IC50	220 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[(S)-(5-chloro-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-4-cyano-3-methylbenzamide	IC50	227 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
[(2R)-2-amino-3-hydroxy-2-[2-(4-octylphenyl)ethyl]propoxy]phosphonic acid	KI	277 nM
1-(5,6-dichloro-3-pyridinyl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	300 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
N-[(S)-(5-bromo-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-4-cyano-3-methylbenzamide	IC50	308 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
4-chloro-N-[(S)-(5-chloro-3-fluoro-2-pyridinyl)-(4-chlorophenyl)methyl]-3-methylbenzamide	IC50	332 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
3-chloro-N-[(S)-(5-chloro-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-4-fluorobenzamide	IC50	347 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
1-(4-chloro-5-methylthiophen-2-yl)-3-[(1,3-dimethyl-4-propan-2-ylpyrazolo[5,4-b]pyridin-6-yl)-(2-hydroxyethyl)amino]urea	IC50	360 nM	US-9663511: Sphingosine 1-phosphate receptor antagonists
methyl N-[2-[[2-[[amino(phenyl)methylidene]amino]-1-(3-chlorophenyl)-2-oxoethyl]amino]-1-(3-chlorophenyl)-2-oxoethyl]carbamate	IC50	390 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[2-[[amino(phenyl)methylidene]amino]-1-(3-chlorophenyl)-2-oxoethyl]-3,4-dichlorobenzamide	IC50	392 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[2-[[amino(phenyl)methylidene]amino]-1-(3,4-dichlorophenyl)-2-oxoethyl]-3,4-dichlorobenzamide	IC50	426 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[(S)-(5-chloro-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-4-cyano-3,5-dimethylbenzamide	IC50	452 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[2-[[amino(phenyl)methylidene]amino]-1-(3-chlorophenyl)-2-oxoethyl]-3-chlorobenzamide	IC50	456 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
tert-butyl N-[2-[[2-[[amino(phenyl)methylidene]amino]-1-(3-chlorophenyl)-2-oxoethyl]amino]-1-(3-chlorophenyl)-2-oxoethyl]carbamate	IC50	475 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
3-chloro-4-cyano-N-[(S)-(3,4-dichlorophenyl)-(5-methyl-2-pyridinyl)methyl]benzamide	IC50	505 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[2-[[amino(phenyl)methylidene]amino]-2-oxo-1-phenylethyl]-3-bromobenzamide	IC50	564 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[(S)-(5-bromo-2-pyridinyl)-(3,4-dichlorophenyl)methyl]-4-cyano-3-fluorobenzamide	IC50	566 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
3-chloro-N-[(S)-(5-chloro-2-pyridinyl)-(4-methylphenyl)methyl]-4-cyanobenzamide	IC50	604 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
3-chloro-N-[(S)-(4-chloro-3-fluorophenyl)-(5-chloro-2-pyridinyl)methyl]-4-cyanobenzamide	IC50	810 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[2-[[amino(phenyl)methylidene]amino]-1-(3,4-dichlorophenyl)-2-oxoethyl]-3-chlorobenzamide	IC50	823 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
N-[(S)-(5-chloro-3-fluoro-2-pyridinyl)-(4-chlorophenyl)methyl]-4-cyano-3-methylbenzamide	IC50	878 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders
1-(3,4-dichlorophenyl)-3-[phenyl-(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]urea	IC50	881 nM	US-10323029: Sphinogosine-1-phosphate receptor modulators for treatment of cardiopulmonary disorders

ChEMBL bioactivities

674 potent at pChembl≥5 of 792 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.49	IC50	0.032	nM	CHEMBL4874736
9.64	IC50	0.23	nM	CHEMBL225155
9.52	IC50	0.3	nM	CHEMBL4864274
9.49	IC50	0.32	nM	CHEMBL4874736
9.46	IC50	0.35	nM	CHEMBL225155
9.37	IC50	0.43	nM	CHEMBL4877932
9.31	Kd	0.49	nM	CHEMBL5172220
9.21	IC50	0.61	nM	CHEMBL4850513
9.20	Kd	0.63	nM	CHEMBL5193759
9.16	Kd	0.69	nM	CHEMBL5206290
9.15	IC50	0.7	nM	CHEMBL118860
9.15	EC50	0.7	nM	CHEMBL225155
9.14	Kd	0.73	nM	CHEMBL5208524
9.11	IC50	0.77	nM	CHEMBL4847056
9.11	IC50	0.77	nM	CHEMBL114606
9.10	IC50	0.8	nM	CHEMBL117130
9.10	IC50	0.8	nM	CHEMBL119440
9.10	IC50	0.8	nM	CHEMBL4852127
9.06	Kd	0.88	nM	CHEMBL5181599
9.05	Kd	0.89	nM	CHEMBL5206026
9.01	Kd	0.98	nM	CHEMBL3401388
9.00	IC50	1	nM	CHEMBL119116
8.94	Kd	1.15	nM	CHEMBL5201190
8.92	IC50	1.2	nM	CHEMBL5755435
8.89	EC50	1.3	nM	CHEMBL225155
8.89	IC50	1.3	nM	CHEMBL4874151
8.89	IC50	1.3	nM	CHEMBL5076031
8.85	IC50	1.4	nM	CHEMBL119382
8.82	IC50	1.5	nM	CHEMBL441826
8.77	IC50	1.7	nM	CHEMBL119413
8.77	IC50	1.7	nM	CHEMBL333335
8.74	IC50	1.8	nM	CHEMBL323617
8.74	IC50	1.8	nM	CHEMBL331054
8.74	IC50	1.8	nM	CHEMBL432067
8.72	IC50	1.9	nM	CHEMBL118815
8.70	IC50	2	nM	CHEMBL119873
8.68	IC50	2.1	nM	CHEMBL4860509
8.68	IC50	2.1	nM	CHEMBL5082556
8.66	EC50	2.2	nM	CHEMBL225155
8.65	IC50	2.25	nM	CHEMBL4868016
8.64	IC50	2.3	nM	CHEMBL3703203
8.59	IC50	2.6	nM	CHEMBL116981
8.59	IC50	2.6	nM	CHEMBL5192525
8.54	IC50	2.9	nM	CHEMBL119354
8.54	EC50	2.9	nM	CHEMBL225155
8.52	IC50	3	nM	CHEMBL332667
8.52	IC50	3	nM	CHEMBL3401386
8.52	IC50	3	nM	CHEMBL3703198
8.51	IC50	3.1	nM	CHEMBL4877928
8.49	IC50	3.2	nM	CHEMBL5082556

PubChem BioAssay actives

493 with measured affinity, of 1161 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-(2-chloro-6-ethoxy-4-pyridinyl)-3-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]urea	1776576: Antagonist activity at recombinant human S1P2 receptor in HFL1 cells assessed as inhibition of EC80 S1P-induced IL8 release incubated for 16 to 24 hrs in absence of HSA by ELISA	ic50	<0.0001	uM
[(E,2S,3R)-2-amino-3-hydroxyoctadec-4-enyl] dihydrogen phosphate	204174: Inhibition of [33P]-S1P binding to human Sphingosine 1-phosphate receptor 5 expressed on CHO cell membranes	ic50	0.0002	uM
1-(3,5-dichlorophenyl)-3-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]urea	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0003	uM
5,6-dichloro-N-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]-1H-benzimidazol-2-amine	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0004	uM
4-(cyclohexylmethyl)-N-[3-(4-fluorophenoxy)-5-[4-(methylcarbamoyl)phenoxy]phenyl]piperazine-1-carboxamide	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0005	uM
4,6-dichloro-N-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]-1H-indole-2-carboxamide	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0006	uM
4-(2-ethylbutylamino)-N-[3-(4-fluorophenoxy)-5-pyridin-4-yloxyphenyl]piperidine-1-carboxamide	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0006	uM
3-[(4-nonylphenyl)methylamino]propylphosphonic acid	204171: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0007	uM
4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-[4-(4-methylpiperazine-1-carbonyl)phenoxy]phenyl]piperazine-1-carboxamide	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0007	uM
4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-[4-(methylcarbamoyl)phenoxy]phenyl]piperazine-1-carboxamide	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0007	uM
3-[(3,5-dimethyl-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0008	uM
1-(2,6-dichloro-4-pyridinyl)-3-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]urea	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0008	uM
1-(2,6-dichloro-4-pyridinyl)-3-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]amino]urea	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0008	uM
[2-amino-1-hydroxy-4-(4-octylphenyl)butan-2-yl] dihydrogen phosphate	204171: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0008	uM
[2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butyl] dihydrogen phosphate	204174: Inhibition of [33P]-S1P binding to human Sphingosine 1-phosphate receptor 5 expressed on CHO cell membranes	ic50	0.0008	uM
4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-pyridin-4-yloxyphenyl]piperazine-1-carboxamide	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0009	uM
4-[3-[[4-(2-ethylbutyl)piperazine-1-carbonyl]amino]-5-(4-fluorophenoxy)phenoxy]benzoic acid	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0009	uM
3-[(3,5-dichloro-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0010	uM
4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-pyridin-4-yloxyphenyl]-4-hydroxypiperidine-1-carboxamide	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0010	uM
tert-butyl 4-[[3-(4-fluorophenoxy)-5-[4-(methylcarbamoyl)phenoxy]phenyl]carbamoyl]piperazine-1-carboxylate	1848143: Binding affinity to S1PR2 (unknown origin) assessed as dissociation constant by surface plasmon resonance analysis	kd	0.0011	uM
2-[1-[[7-chloro-6-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxocinnolin-3-yl]propanoic acid	1823899: Antagonist activity at human S1P2 in HFL1 cells assessed as inhibition of EC80 S1P-induced IL8 release incubated for 16 to 24 hrs by ELISA	ic50	0.0013	uM
4,6-dichloro-N-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0013	uM
3-[[4-(2-heptyltetrazol-5-yl)phenyl]methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0014	uM
3-[(3-bromo-4-decoxy-5-methoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0015	uM
3-[(3-chloro-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0017	uM
3-[(4-nonoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0017	uM
[2-amino-4-(4-octylphenyl)butyl] dihydrogen phosphate	204174: Inhibition of [33P]-S1P binding to human Sphingosine 1-phosphate receptor 5 expressed on CHO cell membranes	ic50	0.0018	uM
3-[(3-methyl-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0018	uM
3-[[4-(5-heptyl-1,2,4-oxadiazol-3-yl)phenyl]methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0018	uM
3-[(3-bromo-5-methoxy-4-undecoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0019	uM
3-[(3-fluoro-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0020	uM
(2S)-2-[1-[[7-chloro-6-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxocinnolin-3-yl]propanoic acid	1823899: Antagonist activity at human S1P2 in HFL1 cells assessed as inhibition of EC80 S1P-induced IL8 release incubated for 16 to 24 hrs by ELISA	ic50	0.0021	uM
ethyl 6-[2-[(2,6-dichloro-4-pyridinyl)carbamoyl]hydrazinyl]-4-methylpyridine-2-carboxylate	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0021	uM
6-chloro-N-[[5-(1,3-dimethylpyrazol-4-yl)-4-methyl-2-pyridinyl]methyl]-4-ethoxy-1H-imidazo[4,5-c]pyridin-2-amine	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0022	uM
2-[4-[3-(4-fluorophenoxy)-5-[[4-hydroxy-4-(2-methylpropyl)piperidine-1-carbonyl]amino]phenoxy]phenyl]-2-methylpropanoic acid	1275513: Antagonist activity at S1P2 receptor (unknown origin) expressed in CHO cells assessed as inhibition of S1P-induced increase in intracellular calcium ion concentration by Fura-2AM based fluorescence analysis	ic50	0.0023	uM
3-[[4-(4-hexylphenyl)phenyl]methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0026	uM
N-(5-chloro-2,4-dimethoxyphenyl)-2-[3-[2-(4-hydroxyanilino)-2-oxoethyl]-2,4-dioxoquinazolin-1-yl]acetamide	1853948: Displacement of [32P]S1P from human recombinant S1PR2 incubated for 60 mins by competitive binding assay based scintillation counter	ic50	0.0026	uM
3-[(3-bromo-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0029	uM
3-[(3,5-dibromo-4-octoxyphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0030	uM
4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-[4-(methylcarbamoyl)phenoxy]phenyl]-4-hydroxypiperidine-1-carboxamide	1193526: Displacement of [33P]-S1P from human S1P2 receptor expressed in CHOK1 cells after 60 mins by scintillation counting analysis	ic50	0.0030	uM
1-(2,6-dichloro-4-pyridinyl)-3-[[4-methyl-6-(1-methylpyrazol-4-yl)-2-pyridinyl]amino]urea	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0031	uM
(2R)-2-[4-[[6-chloro-5-(cyclopropylmethoxy)indazol-2-yl]methyl]-1-oxophthalazin-2-yl]propanoic acid	1823893: Antagonist activity at human S1P2 receptor expressed in CHO cells assessed as inhibition of calcium flux	ic50	0.0032	uM
2-[1-[[6-(cyclopropylmethoxy)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxocinnolin-3-yl]propanoic acid	1823893: Antagonist activity at human S1P2 receptor expressed in CHO cells assessed as inhibition of calcium flux	ic50	0.0034	uM
1-(2,6-dichloro-4-pyridinyl)-3-[[4-methyl-5-(1-methylpyrazol-4-yl)-2-pyridinyl]amino]urea	1776574: Antagonist activity at recombinant human S1P2 receptor expressed in human CHO cells assessed as EC80 S1P-induced activation incubated for 4 hrs in presence of [35S]GTPgammaS by Topcount reader	ic50	0.0034	uM
[(Z)-2-amino-3-hydroxyoctadec-4-enyl] dihydrogen phosphate	1798300: [32P] S1P Binding Assay from Article 10.1016/j.bmc.2004.10.008: “Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate.”	ki	0.0034	uM
2-chloro-4-[3-(4-fluorophenoxy)-5-[[4-hydroxy-4-(2-methylpropyl)piperidine-1-carbonyl]amino]phenoxy]benzoic acid	1275513: Antagonist activity at S1P2 receptor (unknown origin) expressed in CHO cells assessed as inhibition of S1P-induced increase in intracellular calcium ion concentration by Fura-2AM based fluorescence analysis	ic50	0.0036	uM
N-[3-(4-carbamoylphenoxy)-5-(4-fluorophenoxy)phenyl]-4-(2-ethylbutyl)-4-hydroxypiperidine-1-carboxamide	1193526: Displacement of [33P]-S1P from human S1P2 receptor expressed in CHOK1 cells after 60 mins by scintillation counting analysis	ic50	0.0037	uM
3-[(3-bromo-5-methoxy-4-nonoxyphenyl)methylamino]propylphosphonic acid	204173: Binding affinity towards human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0039	uM
3-[(4-nonanoylphenyl)methylamino]propylphosphonic acid	204172: Binding affinity to human sphingosine 1-phosphate receptor 5 expressed in CHO cells was determined by using [33P]-S1P as radioligand	ic50	0.0040	uM
4-[3-(4-fluorophenoxy)-5-[[4-hydroxy-4-(2-methylpropyl)piperidine-1-carbonyl]amino]phenoxy]benzoic acid	1275513: Antagonist activity at S1P2 receptor (unknown origin) expressed in CHO cells assessed as inhibition of S1P-induced increase in intracellular calcium ion concentration by Fura-2AM based fluorescence analysis	ic50	0.0040	uM

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sphingosine 1-phosphate	decreases reaction, increases expression, increases uptake	2
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects cotreatment, affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	affects cotreatment, affects expression	1
Leflunomide	increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases expression	1
Cantharidin	increases expression	1
Diazinon	increases methylation	1
Estradiol	increases expression	1
Methapyrilene	increases methylation	1
Methotrexate	increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Nickel	increases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Smoke	decreases expression	1
Taurocholic Acid	increases expression, increases reaction, increases phosphorylation, increases activity, increases uptake	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

147 unique, capped per target: 78 functional, 69 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1051868	Functional	Ratio of agonistic EC50 for S1P to compound for human S1P2 receptor by [35S]GTPgammaS binding assay	Synthesis and biological evaluation of sphingosine kinase substrates as sphingosine-1-phosphate receptor prodrugs. — Bioorg Med Chem
CHEMBL1111161	Binding	Displacement of [33P]S1P from human recombinant S1P2 receptor expressed in HEK cells by scintillation counting	2-imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists. — J Med Chem

Cellosaurus cell lines

5 cell lines: 2 spontaneously immortalized cell line, 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9R7	Ubigene HEK293 S1PR2 KO	Transformed cell line	Female
CVCL_KA68	CHO-K1/EDG5/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KW96	PathHunter CHO-K1 EDG5 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LA24	PathHunter U2OS EDG5 Activated GPCR Internalization	Cancer cell line	Female
CVCL_ZK38	Tango EDG5-bla U2OS	Cancer cell line	Female

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations