SPHK2

Summary

SPHK2 (sphingosine kinase 2, HGNC:18859) is a protein-coding gene on chromosome 19q13.33, encoding Sphingosine kinase 2 (Q9NRA0). Catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions.

This gene encodes one of two sphingosine kinase isozymes that catalyze the phosphorylation of sphingosine into sphingosine 1-phosphate. Sphingosine 1-phosphate mediates many cellular processes including migration, proliferation and apoptosis, and also plays a role in several types of cancer by promoting angiogenesis and tumorigenesis. The encoded protein may play a role in breast cancer proliferation and chemoresistance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 56848 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 145 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_020126

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18859
Approved symbol	SPHK2
Name	sphingosine kinase 2
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000063176
Ensembl biotype	protein_coding
OMIM	607092
Entrez	56848

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 17 protein_coding, 1 nonsense_mediated_decay, 1 non_stop_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000245222, ENST00000340932, ENST00000426514, ENST00000593308, ENST00000597434, ENST00000598088, ENST00000598574, ENST00000599029, ENST00000599033, ENST00000599748, ENST00000600537, ENST00000601704, ENST00000601712, ENST00000860464, ENST00000860465, ENST00000860466, ENST00000860467, ENST00000860468, ENST00000931808, ENST00000931809, ENST00000931810

RefSeq mRNA: 5 — MANE Select: NM_020126 NM_001204158, NM_001204159, NM_001204160, NM_001243876, NM_020126

CCDS: CCDS12727, CCDS59404, CCDS59405, CCDS74414

Canonical transcript exons

ENST00000245222 — 7 exons

Exon	Start	End
ENSE00001764825	48628681	48630405
ENSE00003480637	48620402	48620553
ENSE00003506546	48625891	48626362
ENSE00003514698	48628162	48628277
ENSE00003637281	48627975	48628069
ENSE00003749824	48627692	48627841
ENSE00003894131	48619506	48619543

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 93.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9496 / max 66.3095, expressed in 1781 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176808	4.3598	1680
176812	3.4892	1243
176810	1.7805	1157
208887	0.7165	443
176809	0.4892	255
176814	0.0741	34
176813	0.0240	10
176811	0.0163	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	93.86	gold quality
right frontal lobe	UBERON:0002810	92.10	gold quality
cingulate cortex	UBERON:0003027	90.49	gold quality
anterior cingulate cortex	UBERON:0009835	90.29	gold quality
prefrontal cortex	UBERON:0000451	90.14	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.30	gold quality
right lobe of liver	UBERON:0001114	89.21	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.95	gold quality
metanephros cortex	UBERON:0010533	88.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.15	gold quality
neocortex	UBERON:0001950	88.01	gold quality
ileal mucosa	UBERON:0000331	87.90	gold quality
frontal cortex	UBERON:0001870	87.88	gold quality
cerebellar hemisphere	UBERON:0002245	87.57	gold quality
cerebellar cortex	UBERON:0002129	87.49	gold quality
spinal cord	UBERON:0002240	87.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.23	gold quality
hypothalamus	UBERON:0001898	87.07	gold quality
left testis	UBERON:0004533	86.95	gold quality
transverse colon	UBERON:0001157	86.75	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.74	gold quality
right testis	UBERON:0004534	86.42	gold quality
cerebral cortex	UBERON:0000956	86.33	gold quality
substantia nigra	UBERON:0002038	86.31	gold quality
Ammon’s horn	UBERON:0001954	86.28	gold quality
amygdala	UBERON:0001876	86.16	gold quality
right lobe of thyroid gland	UBERON:0001119	85.82	gold quality
body of stomach	UBERON:0001161	85.79	gold quality
cerebellum	UBERON:0002037	85.74	gold quality
small intestine	UBERON:0002108	85.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

44 targeting SPHK2, 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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6809-3P	99.91	71.45	3814
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-4753-3P	99.90	71.03	3786
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-4473	98.89	69.10	652
HSA-MIR-4656	98.79	66.22	1306

Literature-anchored findings (GeneRIF, showing 40)

• although both sphingosine kinase type 1 (SphK1) and type 2 (SphK2) can phosphorylate FTY720 with low efficiency, SphK2 is much more effective than SphK1 (PMID:14596938)
• Sphingosine kinase 2 plays an important role in migration of MDA-MB-453 cells toward EGF. (PMID:15951439)
• the N-terminal-extended form of sphingosine kinase 2 has a role in serum-dependent regulation of cell proliferation and apoptosis (PMID:16103110)
• hSphK2 is phosphorylated on Ser-351 and Thr-578 by ERK1 and phosphorylation of these residues is important for EGF-stimulated migration of MDA-MB-453 cells (PMID:17311928)
• PKD is a physiologically relevant enzyme for SPHK2 phosphorylation, which leads to its nuclear export for subsequent cellular signaling. (PMID:17635916)
• Sphingosine kinase 2, but not sphingosine kinase 1, acted in concert with SPP-1 to regulate recycling of sphingosine into ceramide. (PMID:17895250)
• These data suggest that differential formation of sphingosine-1-phosphate by SphK1 and SphK2 has distinct and important actions in human mast cells. (PMID:18178871)
• a novel mechanism of regulation of both SK1 and SK2 that is mediated by their interaction with eEF1A. (PMID:18263879)
• A lipid binding domain in Sphk2 that is important for the enzyme’s sub-cellular localisation was identified. (PMID:19168031)
• Results indicate that SPHK1 and 2 isoforms and neutral sphingomyelinase contribute to the regulation of chemosensitivity by controlling ceramide formation and the downstream Akt pathway in human colon cancer cells. (PMID:19240026)
• SPHK2 may regulate the autonomous proliferation of synovial fibroblasts as one of the predisposing genes to rheumatoid arthritis (PMID:19490468)
• Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. (PMID:20197547)
• pharmacological inhibition of Sphk2 with the orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemo- and endocrine therapy- resistant breast cancer. (PMID:21307639)
• SK2 functions as a pro-survival protein and is involved in promoting actin rearrangement into membrane ruffles/lamellipodia in response to sphingosine 1-phosphate in MCF-7 breast cancer cells. (PMID:21620961)
• Sphingosine kinase 2 might function simply to dynamically regulate sphingosine-S1P cycling. (PMID:23314175)
• The function of SphK1 and SphK2 can be interchangeable in mast cells and is species and cell type determined. (PMID:23359503)
• SphK2 plays a controversial role in arthritis. (PMID:23881266)
• the expression of SphK2 parallels the progression of NSCLC. The expression of SphK2 might represent a novel and potentially independent biomarker for the prognosis of patients with NSCLC. (PMID:23918304)
• these results implicate interrelated mechanisms and SPHK2 inhibition in the induction of PEL cell death by ABC294640 and rationalize evaluation of ABC294640 in clinical trials for the treatment of KSHV-associated lymphoma. (PMID:24140934)
• Silencing of sphingosine kinase 2 (SphK-2) also blocked HDL-induced COX-2/PGI-2 activation. (PMID:24385109)
• IGF1R mediates insulin-stimulated phosphorylation of both SphK1 and SphK2. (PMID:24422628)
• SK2 prevents the nuclear translocation of Y416 phosphorylated c-Src and this appears to be independent of S1P4 and might involve an intracellular S1P-dependent mechanism, which is resistant to exogenously added S1P. (PMID:24486401)
• Results demonstrated that SK2 regulates MYC, which has a pivotal role in hematologic malignancies. (PMID:24686171)
• SPHK2 regulates apoptosis in colon cancer cells. (PMID:24709100)
• 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)
• These data illuminate a novel survival mechanism and potential therapeutic target for KSHV-infected endothelial cells: SphK2-associated maintenance of viral latency (PMID:25010828)
• Down-regulation of SphK2 increased the effects of all-trans-retinoic acid on colon cancer cells. (PMID:25455157)
• Because of the unique relationship observed after serum depletion, we examined effects of siRNA for SPHK2, and found the role of SPHK2 as a growth or survival factor but not a cell proliferation inhibitor in FCS(-) culture (PMID:25808826)
• results define new mechanistic insights for EGF-mediated invasion and novel actions of SK2 (PMID:26209696)
• Targeting of SphK2 by ABC294640 potently inhibits colorectal cancer cell growth both in vitro and in vivo. (PMID:26337959)
• ABC294640 may reduce the proliferative capacity of castration-resistant prostate cancer cells through inhibition of both sphingosine kinase 2 and dihydroceramide desaturase. (PMID:26494858)
• In this study, we describe the findings that overexpression of SphK2 promotes chemoresistance in non-small cell lung cancer (NSCLC) cells. Inhibition of SphK2 might be considered as a strategy in NSCLC treatment with gefitinib (PMID:26628299)
• the pathogenesis of CRC maybe mediated by SphK2, and SphK2 could represent a selective target for the molecularly targeted treatments of CRC (PMID:26733171)
• data suggest that in vitro inhibition of SK-2, can compromise the integrity of the EC monolayer (PMID:26822263)
• increased SK and SPL mRNA expression along with reduced sphingosine 1-phosphate levels were more commonly observed in hepatocellular carcinoma tissues. (PMID:26886371)
• The analysis suggests that the catalytic function and regulation of SPHK1 and SPHK2 might be dependent on their conformational mobility. (Review) (PMID:27021309)
• miR-613 functions as a tumor suppressor in papillary thyroid carcinoma and its suppressive effect is mediated by repressing SphK2 expression (PMID:27223438)
• Data show that inhibition of sphingosine kinase-2 by ABC294640 is synergistically cytotoxic with gemcitabine toward three pancreatic cancer cell lines, resulting in decreased expression of both ribonucleotide reductase regulatory subunit M2 (RRM2) and c-MYC protein (Myc) in all three cell lines. (PMID:27517489)
• this study shows that SK2 can have a direct role in promoting oncogenesis (PMID:27588496)
• SphKs/Sphingosine-1-phosphate signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells. (PMID:28108260)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	sphk2	ENSDARG00000069893
mus_musculus	Sphk2	ENSMUSG00000057342
rattus_norvegicus	Sphk2	ENSRNOG00000021032
drosophila_melanogaster	Sk1	FBGN0030300
drosophila_melanogaster	Cerk	FBGN0037315
drosophila_melanogaster	Sk2	FBGN0052484
caenorhabditis_elegans		WBGENE00007918
caenorhabditis_elegans	cerk-1	WBGENE00020398

Paralogs (4): AGK (ENSG00000006530), CERK (ENSG00000100422), SPHK1 (ENSG00000176170), CERKL (ENSG00000188452)

Protein

Protein identifiers

Sphingosine kinase 2 — Q9NRA0 (reviewed: Q9NRA0)

All UniProt accessions (8): Q9NRA0, A0A075B7A1, E7ET12, E9PCV4, M0QXX5, M0QZP3, M0R0E9, M0R344

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-dihydrosphingosine, D-erythro-sphingosine and L-threo-dihydrosphingosine. Binds phosphoinositides. In contrast to prosurvival SPHK1, has a positive effect on intracellular ceramide levels, inhibits cells growth and enhances apoptosis. In mitochondria, is important for cytochrome-c oxidase assembly and mitochondrial respiration. The SPP produced in mitochondria binds PHB2 and modulates the regulation via PHB2 of complex IV assembly and respiration. In nucleus, plays a role in epigenetic regulation of gene expression. Interacts with HDAC1 and HDAC2 and, through SPP production, inhibits their enzymatic activity, preventing the removal of acetyl groups from lysine residues with histones. Up-regulates acetylation of histone H3-K9, histone H4-K5 and histone H2B-K12. In nucleus, may have an inhibitory effect on DNA synthesis and cell cycle. In mast cells, is the main regulator of SPP production which mediates calcium influx, NF-kappa-B activation, cytokine production, such as TNF and IL6, and degranulation of mast cells. In dopaminergic neurons, is involved in promoting mitochondrial functions regulating ATP and ROS levels. Also involved in the regulation of glucose and lipid metabolism.

Subunit / interactions. Interacts with histone H3. Interacts with HDAC1, HDAC2, MBD2 and SIN3A. Interacts with EEF1A1; the interaction enhances SPHK2 kinase activity. Interacts with PHB2.

Subcellular location. Cytoplasm. Nucleus. Endoplasmic reticulum. Mitochondrion inner membrane Lysosome membrane.

Tissue specificity. Mainly expressed in adult kidney, liver, and brain. Expressed in cerebral cortex and hippocampus (at protein level). Isoform 1 is the predominant form expressed in most tissues.

Post-translational modifications. Phosphorylated by PKD on Ser-419 and Ser-421 upon PMA treatment. Phosphorylation induces export from the nucleus to the cytoplasm. Phosphorylated by MAPK1 and MAPK2 at Ser-387 and Thr-614, phosphorylation is induced by agonists such as EGF and PMA and increases kinase activity. Cleaved by CASP1 in apoptotic cells. The truncated form is released from cells.

Disease relevance. In patients with Alzheimer’s disease brains, may be preferentially localized in the nucleus. Cytosolic expression decrease correlates with the density of amyloid deposits.

Activity regulation. Inhibited by sulfatide. Kinase activity is increased by phosphorylation by MAPK2 upon PMA or EGF treatments.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NRA0-1	1, SK2B, SK2-L	yes
Q9NRA0-2	2, SK2A, SK2-S
Q9NRA0-3	3
Q9NRA0-4	4
Q9NRA0-5	5

RefSeq proteins (5): NP_001191087, NP_001191088, NP_001191089, NP_001230805, NP_064511* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001206	Diacylglycerol_kinase_cat_dom	Domain
IPR016064	NAD/diacylglycerol_kinase_sf	Homologous_superfamily
IPR017438	ATP-NAD_kinase_N	Homologous_superfamily
IPR045540	YegS/DAGK_C	Domain
IPR050187	Lipid_Phosphate_FormReg	Family

Pfam: PF00781, PF19279

Enzyme classification (BRENDA):

• EC 2.7.1.91 — sphingosine kinase (BRENDA: 15 organisms, 102 substrates, 384 inhibitors, 74 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.017–3.8	22
D-ERYTHRO-SPHINGOSINE	0.0025–0.108	12
SPHINGOSINE	0.005–0.108	12
D-(+)-ERYTHRO-SPHINGANINE	0.0034–0.1	4
FTY720	0.018–0.785	4
NITROBENZOXADIAZOLE-LABELED SPHINGOSINE	1–3.6	4
D-ERYTHROSPHINGANINE	0.016	1
DL-ERYTHRO-DIHYDROSPHINGOSINE	0.02	1
L-(-)-THREO-SPHINGANINE	1	1
SPHINGANINE	0.09	1

Catalyzed reactions (Rhea), 4 shown:

• sphinganine + ATP = sphinganine 1-phosphate + ADP + H(+) (RHEA:15465)
• (4R)-hydroxysphinganine + ATP = (4R)-hydroxysphinganine 1-phosphate + ADP + H(+) (RHEA:33563)
• sphing-4-enine + ATP = sphing-4-enine 1-phosphate + ADP + H(+) (RHEA:35847)
• a sphingoid base + ATP = a sphingoid 1-phosphate + ADP + H(+) (RHEA:51496)

UniProt features (45 total): mutagenesis site 11, binding site 9, modified residue 7, splice variant 5, region of interest 3, compositionally biased region 3, short sequence motif 2, chain 1, domain 1, active site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRA0-F1	77.65	0.62

Functional residue map

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

Catalytic / active sites (1): 247 (proton donor/acceptor)

Ligand- & substrate-binding residues (9): 188–190; 220–224; 245–248; 252; 277–279; 344; 351; 357; 622–624

Post-translational modifications (7): 387, 393, 399, 419, 421, 477, 614

Mutagenesis-validated functional residues (11):

Position	Phenotype
138	abolishes cleavage and secretion in apoptotic cells. no effect on kinase activity.
212	decreases spp production in nucleus. abolishes increase of histone acetylation. no effect on association with histone 3.
220	loss of location to cell membrane. not secreted. no effect on kinase activity.
387	strongly reduces phosphorylation levels.
419–421	abolishes nuclear export in response to pma treatment.
423–425	abolishes nuclear export.
437	reduces phosphorylation levels.
466	reduces phosphorylation levels.
477	reduces phosphorylation levels.
552	no effect on cleavage and secretion in apoptotic cells. no effect on kinase activity.
614	abolishes phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1660661	Sphingolipid de novo biosynthesis
R-HSA-1430728	Metabolism
R-HSA-428157	Sphingolipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 348 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, AAGCAAT_MIR137, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_VACUOLAR_MEMBRANE, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_DEGRANULATION, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_SPHINGOLIPID_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_REGULATION_OF_MAST_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP

GO Biological Process (31): blood vessel development (GO:0001568), positive regulation of cytokine production involved in immune response (GO:0002720), sphinganine-1-phosphate biosynthetic process (GO:0006669), sphingosine metabolic process (GO:0006670), brain development (GO:0007420), female pregnancy (GO:0007565), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), sphingolipid biosynthetic process (GO:0030148), negative regulation of cell growth (GO:0030308), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of mast cell activation involved in immune response (GO:0033008), intracellular signal transduction (GO:0035556), positive regulation of apoptotic process (GO:0043065), regulation of canonical NF-kappaB signal transduction (GO:0043122), positive regulation of mast cell degranulation (GO:0043306), transcription initiation-coupled chromatin remodeling (GO:0045815), sphingosine biosynthetic process (GO:0046512), regulation of reactive oxygen species biosynthetic process (GO:1903426), cellular response to phorbol 13-acetate 12-myristate (GO:1904628), regulation of cytochrome-c oxidase activity (GO:1904959), positive regulation of ceramide biosynthetic process (GO:2000304), regulation of ATP biosynthetic process (GO:2001169), sphingosine-1-phosphate receptor signaling pathway (GO:0003376), lipid metabolic process (GO:0006629), obsolete regulation of amide metabolic process (GO:0034248), regulation of apoptotic process (GO:0042981), regulation of lipid biosynthetic process (GO:0046890), regulation of transport (GO:0051049)

GO Molecular Function (11): lipid kinase activity (GO:0001727), ATP binding (GO:0005524), sphingosine kinase activity (GO:0008481), small GTPase binding (GO:0031267), sphingosine-1-phosphate receptor activity (GO:0038036), histone binding (GO:0042393), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), obsolete D-erythro-sphingosine kinase activity (GO:0017050)

GO Cellular Component (12): nucleosome (GO:0000786), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), membrane (GO:0016020), lysosome (GO:0005764), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Sphingolipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
positive regulation of cytokine production	3
intracellular membrane-bounded organelle	3
cytoplasm	3
intracellular anatomical structure	2
vasculature development	1
anatomical structure development	1
cytokine production involved in immune response	1
positive regulation of production of molecular mediator of immune response	1
regulation of cytokine production involved in immune response	1
sphinganine-1-phosphate metabolic process	1
phospholipid biosynthetic process	1
sphingolipid biosynthetic process	1
diol metabolic process	1
sphingoid metabolic process	1
central nervous system development	1
animal organ development	1
head development	1
multi-organism reproductive process	1
multi-multicellular organism process	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
interleukin-13 production	1
regulation of interleukin-13 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
mast cell activation involved in immune response	1
positive regulation of immune effector process	1
positive regulation of mast cell activation	1

Protein interactions and networks

STRING

1718 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPHK2	H3-3A	P06351	963
SPHK2	H3-5	Q6NXT2	963
SPHK2	H3C1	P02295	962
SPHK2	H3-4	Q16695	962
SPHK2	H3C14	Q71DI3	961
SPHK2	H3-7	Q5TEC6	961
SPHK2	S1PR3	Q99500	942
SPHK2	HDAC1	Q13547	932
SPHK2	S1PR4	O95977	922
SPHK2	HDAC2	Q92769	922
SPHK2	SGPL1	O95470	915
SPHK2	SGPP1	Q9BX95	901
SPHK2	S1PR5	Q9H228	898
SPHK2	S1PR2	O95136	890
SPHK2	TLCD3B	Q71RH2	880

IntAct

14 interactions, top by confidence:

A	B	Type	Score
SPHK2	OPTN	psi-mi:“MI:0915”(physical association)	0.560
SPHK2	PPIA	psi-mi:“MI:0407”(direct interaction)	0.440
SPHK2	FYN	psi-mi:“MI:0407”(direct interaction)	0.440
SPHK2	LYN	psi-mi:“MI:0407”(direct interaction)	0.440
FHL2	SPHK2	psi-mi:“MI:0915”(physical association)	0.400
RPL15	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
C2CD4A	PRKCI	psi-mi:“MI:0914”(association)	0.350
NEUROG3	MYO9A	psi-mi:“MI:0914”(association)	0.350
THUMPD3	USP12	psi-mi:“MI:0914”(association)	0.350
hemL	SPHK2	psi-mi:“MI:0915”(physical association)	0.000
SPHK2	astD	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): SPHK2 (Affinity Capture-MS), SPHK2 (Negative Genetic), SPHK2 (Negative Genetic), SPHK2 (Negative Genetic), SPHK2 (Positive Genetic), SPHK2 (Positive Genetic), SPHK2 (Positive Genetic), SPHK2 (Affinity Capture-Western), BCL2 (Affinity Capture-Western), SPHK2 (Reconstituted Complex), DYNC1I1 (Affinity Capture-Western), DYNC1LI1 (Affinity Capture-Western), DCTN1 (Affinity Capture-Western), DYNC1I2 (Two-hybrid), DYNC1I2 (Affinity Capture-Western)

ESM2 similar proteins: A1L134, A1L1C2, A6QP75, E1BE10, E2RD63, G5E872, O00587, P56433, P70295, Q0V8G3, Q11128, Q16512, Q28DT3, Q2TBI8, Q32M88, Q3UFB7, Q4R942, Q501J2, Q5E9V4, Q5F2F2, Q5IS64, Q5SWZ9, Q6AYG0, Q6IN84, Q6P9U1, Q8BH73, Q8BNV1, Q8BZG5, Q8IZ69, Q8N2A8, Q8N9H8, Q8NE01, Q8TD43, Q8VHS5, Q8WXI3, Q91ZT7, Q920N2, Q969S8, Q96DC7, Q96NS5

Diamond homologs: C0LT23, O14159, O31502, Q18425, Q6B516, Q6USK2, Q8CI15, Q8TCT0, Q91V26, Q9JIA7, Q9LRB0, Q9NRA0, Q9NYA1, F2Y4A3, Q06147, Q10123, Q7ZW00, Q7ZYJ3, Q8K4Q7, Q8L7L1, Q12246, Q86KF9, C6DBD7, O82359, Q02PI7, Q1QUK4, Q2NYP7, Q3BYC8, Q4UZH0, Q5GVG9, Q8PD82, Q8PQ53, Q9HZI3, O34799, Q97QZ6, Q9TZI1

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
MAPK1	up-regulates	SPHK2	phosphorylation
MAPK3	up-regulates	SPHK2	phosphorylation
CASP1	“up-regulates activity”	SPHK2	binding
Gbeta	up-regulates	SPHK2	phosphorylation
ERK1/2	up-regulates	SPHK2	phosphorylation
NEDD4L	“down-regulates quantity by destabilization”	SPHK2	ubiquitination
miR‑137	“down-regulates quantity by destabilization”	SPHK2	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	118
Likely benign	14
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1315 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48619541:G:GT	donor_gain	1.0000
19:48619541:GAGG:G	donor_loss	1.0000
19:48619542:AGGT:A	donor_loss	1.0000
19:48627690:A:AG	acceptor_gain	1.0000
19:48627691:G:GG	acceptor_gain	1.0000
19:48627837:GACAG:G	donor_gain	1.0000
19:48627841:GGTAA:G	donor_loss	1.0000
19:48627842:G:GG	donor_gain	1.0000
19:48627842:GT:G	donor_loss	1.0000
19:48628273:GGGGG:G	donor_gain	1.0000
19:48628274:GGGG:G	donor_gain	1.0000
19:48628274:GGGGG:G	donor_gain	1.0000
19:48628275:GGG:G	donor_gain	1.0000
19:48628275:GGGG:G	donor_gain	1.0000
19:48628275:GGGGT:G	donor_loss	1.0000
19:48628276:GG:G	donor_gain	1.0000
19:48628276:GGG:G	donor_gain	1.0000
19:48628277:GG:G	donor_gain	1.0000
19:48628279:T:G	donor_loss	1.0000
19:48619358:G:T	donor_gain	0.9900
19:48619540:GGAG:G	donor_gain	0.9900
19:48619541:GAG:G	donor_gain	0.9900
19:48619545:T:A	donor_loss	0.9900
19:48620401:GA:G	acceptor_gain	0.9900
19:48625950:GGC:G	donor_gain	0.9900
19:48626339:G:GT	donor_gain	0.9900
19:48627687:CACA:C	acceptor_loss	0.9900
19:48627688:ACAG:A	acceptor_loss	0.9900
19:48627689:CA:C	acceptor_loss	0.9900
19:48627690:AG:A	acceptor_loss	0.9900

AlphaMissense

4097 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48628817:T:A	W337R	0.996
19:48628817:T:C	W337R	0.996
19:48627737:T:C	L186S	0.995
19:48627990:C:A	A226D	0.995
19:48628847:A:C	S347R	0.995
19:48628849:C:A	S347R	0.995
19:48628849:C:G	S347R	0.995
19:48627744:T:A	N188K	0.994
19:48627744:T:G	N188K	0.994
19:48628002:T:A	V230D	0.994
19:48628820:G:C	G338R	0.994
19:48628880:T:C	F358L	0.994
19:48628882:C:A	F358L	0.994
19:48628882:C:G	F358L	0.994
19:48629631:T:C	F608S	0.994
19:48628025:T:A	W238R	0.993
19:48628025:T:C	W238R	0.993
19:48628046:T:C	S245P	0.993
19:48628860:G:T	R351M	0.993
19:48628940:T:G	Y378D	0.993
19:48626308:T:A	W153R	0.992
19:48626308:T:C	W153R	0.992
19:48627740:T:A	V187D	0.992
19:48628038:T:A	V242D	0.992
19:48628245:C:A	N280K	0.992
19:48628245:C:G	N280K	0.992
19:48629634:G:C	R609P	0.992
19:48627999:T:C	L229P	0.991
19:48628821:G:T	G338V	0.991
19:48629399:T:A	W531R	0.991

dbSNP variants (sampled 300 via entrez): RS1000393717 (19:48630499 G>T), RS1000395467 (19:48623732 C>A), RS1000516718 (19:48618471 C>A,T), RS1000743617 (19:48630144 T>C,G), RS1001216090 (19:48617562 G>A), RS1001390918 (19:48622933 T>G), RS1001582568 (19:48629877 G>A,C,T), RS1001586851 (19:48618259 GCAATACTACTAGAACCA>G), RS1001951001 (19:48626452 T>C), RS1002111853 (19:48620760 C>A,T), RS1002181465 (19:48622099 CAA>C,CA,CAAA), RS1002488838 (19:48620970 C>G,T), RS1002691834 (19:48618148 A>C), RS1002853224 (19:48628586 C>T), RS1002968446 (19:48622007 G>A)

Disease associations

OMIM: gene MIM:607092 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001241_6	Bipolar disorder	3.000000e-06
GCST001729_25	Crohn’s disease	1.000000e-15
GCST004626_161	Myeloid white cell count	3.000000e-12
GCST010134_4	Non-oily fish consumption	3.000000e-16
GCST010135_4	Oily fish consumption	2.000000e-16
GCST010140_48	Pork consumption	2.000000e-16
GCST011109_6	Psoriasis	7.000000e-11
GCST90002385_517	High light scatter reticulocyte count	1.000000e-16
GCST90002386_212	High light scatter reticulocyte percentage of red cells	2.000000e-16
GCST90002387_148	Immature fraction of reticulocytes	6.000000e-16
GCST90002388_376	Lymphocyte count	2.000000e-18
GCST90002389_410	Lymphocyte percentage of white cells	1.000000e-24
GCST90002396_44	Mean reticulocyte volume	3.000000e-19
GCST90002398_91	Neutrophil count	4.000000e-25
GCST90002399_442	Neutrophil percentage of white cells	5.000000e-20
GCST90002404_537	Red cell distribution width	3.000000e-09
GCST90002405_554	Reticulocyte count	3.000000e-10
GCST90002406_532	Reticulocyte fraction of red cells	4.000000e-10
GCST90002407_633	White blood cell count	5.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0007986	reticulocyte count
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3023 (SINGLE PROTEIN), CHEMBL4680050 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 677 (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
CHEMBL2158685	ABC-294640	2	677

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Sphingosine kinase

Most potent curated ligand interactions (12 total), top 12:

Ligand	Action	Affinity	Parameter
compound 49 [PMID: 30889352]	Inhibition	7.8	pIC50
compound 59 [PMID: 30889352]	Inhibition	7.77	pIC50
compound 60 [PMID: 30889352]	Inhibition	7.51	pIC50
compound 55 [PMID: 30889352]	Inhibition	7.39	pIC50
SLC4101431	Inhibition	7.05	pKi
SLM6071469	Inhibition	7.05	pKi
compound 27d [PMID: 28231433]	Inhibition	6.84	pIC50
PF-543	Inhibition	6.45	pIC50
MP-A08	Inhibition	5.16	pKi
SKI II	Inhibition	5.1	pKi
opaganib	Inhibition	5.01	pKi
ROMe	Inhibition	4.78	pKi

Binding affinities (BindingDB)

16 measured of 74 human assays (74 total across all organisms); most potent 16 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-(4-dodecylbenzoyl)pyrrolidine-2-carboximidamide	KI	100 nM	US-9688668: Long chain base sphingosine kinase inhibitors
CHEMBL3814083	KI	9800 nM
CHEMBL2158685	KI	9800 nM
(2S)-2-[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide	KI	12000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
heptadecanimidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
1-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
1-[3-(4-undecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
1-[3-(4-dodecylphenyl)-1,2,4-oxadiazol-5-yl]cyclopropane-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
2-[4-(4-octylphenyl)cyclohexyl]guanidine	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
2-[[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl]methyl]guanidine	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
2-[(1S)-1-[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl]ethyl]guanidine	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
2-[(1S)-2-methyl-1-[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl]propyl]guanidine	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
(2S,3S)-3-hydroxy-2-[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
(S)-2-(3-(4-decylphenyl)-1,2,4-oxadiazol- 5-yl)pyrrolidine-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
(2S)-2-[3-(4-decylphenyl)-1,2,4-oxadiazol-5-yl]azetidine-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors
3-[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl]azetidine-1-carboximidamide	KI	55000 nM	US-9688668: Long chain base sphingosine kinase inhibitors

ChEMBL bioactivities

249 potent at pChembl≥5 of 372 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	Ki	0.09	nM	CHEMBL4750447
9.92	Ki	0.12	nM	CHEMBL4782021
9.54	Ki	0.29	nM	CHEMBL4783605
9.52	Ki	0.3	nM	CHEMBL4755938
9.01	Ki	0.98	nM	CHEMBL3814580
8.72	IC50	1.913	nM	CHEMBL5420859
8.62	IC50	2.4	nM	CHEMBL4104017
8.62	IC50	2.404	nM	CHEMBL5407736
8.46	IC50	3.431	nM	CHEMBL5399307
8.44	Ki	3.6	nM	CHEMBL3134157
7.94	IC50	11.46	nM	CHEMBL5405542
7.94	IC50	11.46	nM	CHEMBL4574678
7.80	IC50	16	nM	CHEMBL4574678
7.77	IC50	17	nM	CHEMBL4593030
7.70	IC50	20	nM	CHEMBL2409849
7.70	IC50	20	nM	CHEMBL2409891
7.58	IC50	26	nM	CHEMBL4578165
7.51	IC50	31	nM	CHEMBL4453199
7.50	EC50	32	nM	CHEMBL4593983
7.46	IC50	35	nM	CHEMBL4472026
7.45	IC50	35.78	nM	CHEMBL5439990
7.43	EC50	37	nM	CHEMBL4462152
7.40	IC50	40	nM	CHEMBL2409848
7.40	IC50	40	nM	CHEMBL2409847
7.39	IC50	41	nM	CHEMBL4551657
7.38	IC50	41.62	nM	CHEMBL5433518
7.33	IC50	46.23	nM	CHEMBL5432322
7.31	IC50	49	nM	CHEMBL4456309
7.30	IC50	50	nM	CHEMBL2409850
7.30	EC50	50	nM	CHEMBL4456325
7.26	IC50	55	nM	CHEMBL4551903
7.23	EC50	59	nM	CHEMBL4453931
7.22	IC50	60	nM	CHEMBL552462
7.14	EC50	73	nM	CHEMBL4570134
7.08	EC50	84	nM	CHEMBL4473353
7.05	IC50	90	nM	CHEMBL2409888
7.05	IC50	90	nM	CHEMBL2409870
7.05	IC50	90	nM	CHEMBL2409867
7.05	Ki	90	nM	CHEMBL4076808
7.05	Ki	90	nM	CHEMBL4074731
7.05	Ki	89	nM	CHEMBL4453931
7.00	IC50	100	nM	CHEMBL2409891
6.96	IC50	110	nM	CHEMBL2409889
6.92	IC50	119	nM	CHEMBL4448423
6.84	IC50	145	nM	CHEMBL4063506
6.84	EC50	146	nM	CHEMBL4466495
6.84	IC50	143	nM	CHEMBL4474024
6.83	IC50	148	nM	CHEMBL3763321
6.82	IC50	150	nM	CHEMBL2409883
6.82	IC50	151	nM	CHEMBL4454855

PubChem BioAssay actives

243 with measured affinity, of 900 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
(2S)-2-[3-(1-nonylindol-5-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1730247: Inhibition of recombinant human Sphk2 expressed in baculovirus infected Sf9 insect cells using d-erythro-sphingosine as substrate measured after 20 mins in presence of [gamma-32P]ATP by liquid scintillation counting analysis	ki	0.0001	uM
(2S)-2-[3-(1-decylindol-5-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1730247: Inhibition of recombinant human Sphk2 expressed in baculovirus infected Sf9 insect cells using d-erythro-sphingosine as substrate measured after 20 mins in presence of [gamma-32P]ATP by liquid scintillation counting analysis	ki	0.0001	uM
(2S)-2-[3-(1-dodecylindol-3-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1730247: Inhibition of recombinant human Sphk2 expressed in baculovirus infected Sf9 insect cells using d-erythro-sphingosine as substrate measured after 20 mins in presence of [gamma-32P]ATP by liquid scintillation counting analysis	ki	0.0003	uM
(2S)-2-[3-(1-decylindol-3-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1730247: Inhibition of recombinant human Sphk2 expressed in baculovirus infected Sf9 insect cells using d-erythro-sphingosine as substrate measured after 20 mins in presence of [gamma-32P]ATP by liquid scintillation counting analysis	ki	0.0003	uM
(2S)-2-[3-[6-[[4-(trifluoromethyl)phenyl]methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1730247: Inhibition of recombinant human Sphk2 expressed in baculovirus infected Sf9 insect cells using d-erythro-sphingosine as substrate measured after 20 mins in presence of [gamma-32P]ATP by liquid scintillation counting analysis	ki	0.0010	uM
(2S)-2-[3-(6-butoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1730247: Inhibition of recombinant human Sphk2 expressed in baculovirus infected Sf9 insect cells using d-erythro-sphingosine as substrate measured after 20 mins in presence of [gamma-32P]ATP by liquid scintillation counting analysis	ki	0.0010	uM
[(2R)-1-[[4-[(3-cyclohexylphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1442126: Inhibition of SPHK2 (unknown origin) by FITC-based caliper assay	ic50	0.0017	uM
[(2R)-1-[[4-[(3-propan-2-ylphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1442126: Inhibition of SPHK2 (unknown origin) by FITC-based caliper assay	ic50	0.0017	uM
[(2S)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0019	uM
[(2R)-1-[[4-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1442126: Inhibition of SPHK2 (unknown origin) by FITC-based caliper assay	ic50	0.0024	uM
(2R)-1-[4-[[5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]methoxy]benzoyl]pyrrolidine-2-carboxamide	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0024	uM
[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-[4-[[5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]methoxy]phenyl]methanone	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0034	uM
[(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593544: Inhibition of SK2 (unknown origin)	ki	0.0036	uM
[(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0115	uM
N-(2-amino-2-oxoethyl)-4-[(3-phenylmethoxyphenoxy)methyl]benzamide	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0115	uM
[(2R)-1-[[4-[[3-[(4-fluorophenyl)methylsulfanyl]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0170	uM
(2R,4S)-2-(hydroxymethyl)-1-[2-[4-[[4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]phenyl]ethyl]piperidin-4-ol	1304652: Inhibition of human SphK2 using sphingosine as substrate incubated for 50 mins by scintillation counting analysis in presence of [gamma-33P]ATP	ic50	0.0200	uM
(2R,4S)-1-[2-[4-[[4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]phenyl]ethyl]-2-(hydroxymethyl)piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0200	uM
[(2R)-1-[[4-[(3-benzylsulfanylphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0260	uM
[(2R)-1-[[4-[[3-[(4-chlorophenyl)methylsulfanyl]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0310	uM
(2S)-2-[3-[3-propan-2-yl-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.0320	uM
[(2R)-1-[[4-[[3-(2-phenylethyl)phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0350	uM
N-(2-hydroxyethyl)-4-[[5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl]methoxy]benzamide	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0358	uM
(2S)-2-[3-[3-propyl-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.0370	uM
(2R,4S)-1-[2-[4-[[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]amino]phenyl]ethyl]-2-(hydroxymethyl)piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0400	uM
(2R,4S)-1-[2-[4-[[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]phenyl]ethyl]-2-(hydroxymethyl)piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0400	uM
[(2R)-1-[[4-[[3-[(4-chlorophenyl)methoxy]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0410	uM
N-(2-aminoethyl)-4-[(3-phenylmethoxyphenoxy)methyl]benzamide	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0416	uM
2-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methylamino]acetamide	2012513: Inhibition of SphK2 (unknown origin) using NBD-Sph as substrate by fluorescent plate reader analysis	ic50	0.0462	uM
[(2R)-1-[[4-[[3-[(4-fluorophenyl)methoxy]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0490	uM
(2S)-2-[3-[3-cyclopropyl-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.0500	uM
(2R,4S)-1-[2-[4-[[4-[2-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]phenyl]ethyl]-2-(hydroxymethyl)piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0500	uM
[(2R)-1-[[4-[[3-[(2-fluorophenyl)methoxy]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.0550	uM
(2S)-2-[3-[3-(trifluoromethyl)-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.0590	uM
[4-amino-2-(4-methoxyanilino)-1,3-thiazol-5-yl]-(3,4-dimethoxyphenyl)methanone	1674861: Binding affinity to SphK2 in HEK293 cells assessed as direct target engagement incubated for 24 hrs followed by thermal denaturation at 61 degreeC by ITDRF-CETSA assay	ic50	0.0600	uM
(2S)-2-[3-[3-tert-butyl-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.0730	uM
(2S)-2-[3-[3-prop-2-enyl-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.0840	uM
(2S)-2-[[3-[4-[[4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]phenyl]-1,2,4-oxadiazol-5-yl]methyl]pyrrolidine-1-carboximidamide;hydrochloride	1482717: Inhibition of recombinant human SPHK2 at using sphingosine as substrate after 30 mins in presence of gamma-[32P]-ATP by liquid scintillation counting	ki	0.0900	uM
(2S)-2-[[3-[4-[[4-(4-phenylphenyl)-1,3-thiazol-2-yl]amino]phenyl]-1,2,4-oxadiazol-5-yl]methyl]pyrrolidine-1-carboximidamide;hydrochloride	1482717: Inhibition of recombinant human SPHK2 at using sphingosine as substrate after 30 mins in presence of gamma-[32P]-ATP by liquid scintillation counting	ki	0.0900	uM
(3R,5R)-1-[2-[4-[[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]amino]phenyl]ethyl]-5-(hydroxymethyl)pyrrolidin-3-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0900	uM
(3S,5R)-1-[3-[4-[[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]amino]phenyl]propyl]-5-(hydroxymethyl)pyrrolidin-3-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0900	uM
(2R,4S)-1-[2-[4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenyl]ethyl]-2-(hydroxymethyl)piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.0900	uM
(2R,4S)-2-(hydroxymethyl)-1-[2-[4-[[4-(4-methylphenyl)-1,3-thiazol-2-yl]amino]phenyl]ethyl]piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.1100	uM
[(2R)-1-[[4-[[3-[(4-methoxyphenyl)methoxy]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.1190	uM
[(2R)-1-[[4-[[3-[(3-fluorophenyl)methoxy]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.1430	uM
N-[3-[[4-[[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]phenyl]methoxy]phenyl]benzamide	1442126: Inhibition of SPHK2 (unknown origin) by FITC-based caliper assay	ic50	0.1450	uM
(2S)-2-[3-[3-ethyl-4-[[4-(trifluoromethyl)phenyl]methoxy]phenyl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride	1559946: Inhibition of human SphK2 expressed in Saccharomyces cerevisiae KYA1 assessed as yeast growth measured after 24 hrs	ec50	0.1460	uM
(3S,5R)-5-(hydroxymethyl)-1-[3-[4-[[4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]phenyl]propyl]pyrrolidin-3-ol	1277462: Inhibition of SK2 (unknown origin)	ic50	0.1480	uM
(2R,4S)-1-[2-[4-[[4-(3-chlorophenyl)-1,3-thiazol-2-yl]amino]phenyl]ethyl]-2-(hydroxymethyl)piperidin-4-ol	762558: Inhibition of purified human SphK2 assessed as inhibition of formation of [33P]-S1P after 50 mins by scintillation counting	ic50	0.1500	uM
[(2R)-1-[[4-[[3-[(2-chlorophenyl)methoxy]phenoxy]methyl]phenyl]methyl]pyrrolidin-2-yl]methanol	1593534: Inhibition of recombinant human full-length N-terminal His-tagged SK2 expressed in baculovirus infected Sf9 insect cells using Sph as substrate measured after 30 mins in presence of [gamma32P]ATP by Cerenkov counting analysis	ic50	0.1510	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
Cadmium Chloride	increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
gossypol acetic acid	increases expression	1
ferrous chloride	decreases expression	1
isobutyl alcohol	decreases expression, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Fingolimod Hydrochloride	decreases reaction, increases expression, affects binding, increases reaction, increases phosphorylation	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Cannabidiol	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	affects reaction, increases expression, increases response to substance	1
Gallic Acid	increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Lead	affects expression	1
Methotrexate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Smoke	decreases expression	1

ChEMBL screening assays

192 unique, capped per target: 186 binding, 5 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032134	Binding	Inhibition of SphK2	Iodophenyl tagged sphingosine derivatives: synthesis and preliminary biological evaluation. — Bioorg Med Chem Lett
CHEMBL3106150	ADMET	Prodrug conversion assessed as human SphK2-mediated formation of phosphorylated compound	Discovery of Clinical Candidate GSK1842799 As a Selective S1P1 Receptor Agonist (Prodrug) for Multiple Sclerosis. — ACS Med Chem Lett
CHEMBL807607	Functional	Rate of phosphorylation of labeled sphingosine derivative by by human SPHK-2 expressed in HEK293 cells relative to rate of D-sphingosine	Fluorescence-labeled sphingosines as substrates of sphingosine kinases 1 and 2. — Bioorg Med Chem Lett

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3I2	Abcam HEK293T SPHK2 KO	Transformed cell line	Female
CVCL_D8BD	Ubigene A-549 SPHK2 KO	Cancer cell line	Male
CVCL_D8W4	Ubigene HCT 116 SPHK2 KO	Cancer cell line	Male
CVCL_D9SW	Ubigene HEK293 SPHK2 KO	Transformed cell line	Female
CVCL_E0PU	Ubigene HeLa SPHK2 KO	Cancer cell line	Female
CVCL_E2KR	HAP1 SPHK2 (-) 1	Cancer cell line	Male
CVCL_E2KS	HAP1 SPHK2 (-) 2	Cancer cell line	Male
CVCL_E2KT	HAP1 SPHK2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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