SMPD3

Summary

SMPD3 (sphingomyelin phosphodiesterase 3, HGNC:14240) is a protein-coding gene on chromosome 16q22.1, encoding Sphingomyelin phosphodiesterase 3 (Q9NY59). Catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine.

Enables sphingomyelin phosphodiesterase activity. Involved in sphingomyelin catabolic process. Predicted to be located in plasma membrane. Predicted to be active in cytoplasm. Biomarker of pulmonary emphysema.

Source: NCBI Gene 55512 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 105 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_018667

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14240
Approved symbol	SMPD3
Name	sphingomyelin phosphodiesterase 3
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	NSMASE2
Ensembl gene	ENSG00000103056
Ensembl biotype	protein_coding
OMIM	605777
Entrez	55512

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000219334, ENST00000561749, ENST00000563226, ENST00000563396, ENST00000563455, ENST00000566009, ENST00000566466, ENST00000566723, ENST00000567223, ENST00000567811, ENST00000568373, ENST00000574662, ENST00000879593, ENST00000879594, ENST00000879595, ENST00000879596, ENST00000879597, ENST00000879598, ENST00000879599, ENST00000879600, ENST00000879601, ENST00000879602, ENST00000879603, ENST00000955003, ENST00000955004, ENST00000955005

RefSeq mRNA: 1 — MANE Select: NM_018667 NM_018667

CCDS: CCDS10867

Canonical transcript exons

ENST00000219334 — 9 exons

Exon	Start	End
ENSE00000844383	68370859	68372387
ENSE00000946492	68361603	68361759
ENSE00001175641	68358327	68361307
ENSE00001410269	68448353	68448508
ENSE00001423583	68386598	68386659
ENSE00003468035	68363777	68363866
ENSE00003543111	68364751	68364906
ENSE00003631182	68365017	68365092
ENSE00003694429	68363496	68363559

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 94.32.

FANTOM5 (CAGE): breadth broad, TPM avg 6.5890 / max 458.9678, expressed in 535 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157883	4.5121	448
157865	0.5554	46
157866	0.3877	51
157867	0.3100	49
157884	0.3056	136
157882	0.1653	99
157871	0.1360	70
157864	0.0753	15
157870	0.0413	21
157868	0.0336	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	94.32	gold quality
cortical plate	UBERON:0005343	92.71	gold quality
duodenum	UBERON:0002114	90.58	gold quality
periodontal ligament	UBERON:0008266	90.09	silver quality
thymus	UBERON:0002370	88.97	silver quality
jejunal mucosa	UBERON:0000399	87.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.21	gold quality
small intestine	UBERON:0002108	86.87	gold quality
ganglionic eminence	UBERON:0004023	86.08	gold quality
mucosa of transverse colon	UBERON:0004991	86.01	gold quality
putamen	UBERON:0001874	84.18	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.09	gold quality
rectum	UBERON:0001052	83.90	gold quality
caudate nucleus	UBERON:0001873	83.60	gold quality
transverse colon	UBERON:0001157	83.54	gold quality
adenohypophysis	UBERON:0002196	83.11	gold quality
cerebellar hemisphere	UBERON:0002245	83.09	gold quality
cerebellar cortex	UBERON:0002129	83.06	gold quality
pituitary gland	UBERON:0000007	83.04	gold quality
ileal mucosa	UBERON:0000331	82.86	gold quality
vena cava	UBERON:0004087	82.62	gold quality
cerebellum	UBERON:0002037	82.07	gold quality
nucleus accumbens	UBERON:0001882	82.02	gold quality
gall bladder	UBERON:0002110	81.87	gold quality
body of stomach	UBERON:0001161	81.44	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	81.40	gold quality
jejunum	UBERON:0002115	81.31	gold quality
skin of leg	UBERON:0001511	81.12	gold quality
prefrontal cortex	UBERON:0000451	80.99	gold quality
right frontal lobe	UBERON:0002810	80.84	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-ANND-5	yes	498.97
E-HCAD-4	yes	45.22
E-HCAD-1	yes	15.39
E-CURD-112	yes	14.73
E-MTAB-9067	yes	14.63
E-MTAB-9467	yes	14.56
E-CURD-122	yes	13.86
E-MTAB-8498	yes	13.33
E-ANND-3	yes	9.46
E-HCAD-10	yes	8.46
E-MTAB-6678	yes	5.27
E-GEOD-137537	yes	5.01
E-CURD-88	yes	4.59
E-CURD-79	no	715.48
E-GEOD-124858	no	2.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX2, TP53

miRNA regulators (miRDB)

188 targeting SMPD3, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611

Literature-anchored findings (GeneRIF, showing 38)

• nSMase2 is a structural gene for nSMase, acts as a bona fide N-SMase in cells, and has a role in the regulation of cell growth and cell signaling (PMID:12566438)
• The metabolic and chemical characteristics of SMPD3 are reported. (PMID:16517606)
• Here, we show that this nSMase2 is up-regulated by an oxidant (H(2)O(2)) and is inhibited by an antioxidant (glutathione (GSH)). (PMID:16631623)
• p38 MAPK is an upstream regulator of nSMase2 and there is a role for nSMase2 in pro-inflammatory responses induced by TNF-alpha as a regulator of adhesion proteins. (PMID:17085432)
• These results indicate the presence of NSMASE2 in the inner leaflet of plasma membrane. (PMID:17349629)
• Nucleotide sequencing of the highly conserved SMPD3 gene in a large panel of human cancers revealed mutations in 5 (5%) of 92 acute myeloid leukemias (AMLs) and 8 (6%) of 131 acute lymphoid leukemias (ALLs), but not in other tumor types (PMID:18299447)
• Data show DA remarkably increased the NSMase2 message and protein, whereas little change in NSMase1 and NSMase3 mRNAs. (PMID:19698806)
• Upon urokinase plasminogen activator stimulation, UPAR, Matrix metalloproteinases, integrin alphavbeta3 and NSMASE2 form a signaling complex that take part in mitogenic signaling in ECV304 cells. (PMID:19735728)
• Neutral sphingomyelinase 2 (nSMase2) is a phosphoprotein regulated by calcineurin (PP2B) (PMID:20106976)
• Neutral sphingomyelinase 2 (nSMase2) is the primary neutral sphingomyelinase isoform activated by tumour necrosis factor-alpha. (PMID:21303347)
• nSMase2 is a major component of ATRA-induced growth arrest of MCF-7 cells; S6K is a novel downstream target of nSMase2 (PMID:21536668)
• NSMase-2- and PP2A-dependent regulation of IRAK-1 degradation is a novel mechanism to fine tune the magnitude of IL-1beta response. (PMID:21708940)
• MMP2 and neutral sphingomyelinase-2 play a role in vasculopathy triggered by a humoral immune response in transplants. (PMID:22082680)
• a requirement for nSMase2-mediated cancer cell exosomal miRNAs in the regulation of metastasis through the induction of angiogenesis in inoculated tumors. (PMID:23439645)
• The H2O2-induced src/PDGFRbeta/SK1 signaling cascade was impaired in nSMase2-deficient fro/fro cells and was rescued by exogenous C2Cer that activated src/PDGFRbeta/SK1. (PMID:23651497)
• This is the first report on the critical role of ceramide generated by nSMase2 in stem cell ciliogenesis and differentiation. (PMID:24694597)
• We found upregulation of specific sphingolipid enzymes, namely sphingomyelin synthase 1 (SMS1), sphingomyelinase 3 (SMPD3), and glucosylceramide synthase (GCS) in the endometrium of endometriotic women. (PMID:24960545)
• These results suggest that OTC is a potent stimulant of nSMase-2 expression and that there may be unanticipated complications of OTC supplementation. (PMID:25047167)
• The data shows that nSMase3 acts as a signaling nSMase in skeletal muscle that is essential for TNF-stimulated oxidant activity. (PMID:25180167)
• SMPD3 plays an important role in the release of microRNAs into extracellular spaces. (PMID:25394686)
• nSMase2 involvement in cellular processes including inflammatory signaling, exosome generation, cell growth, and apoptosis, which in turn play important roles in pathologies such as cancer metastasis, Alzheimer’s disease (PMID:25465297)
• nSMase2 is a novel p53 target gene, regulated by the DNA damage pathway to induce cell growth arrest. (PMID:26512957)
• low oxLDL concentration triggers sprouting angiogenesis that involves ROS-induced activation of the neutral sphingomyelinase-2/sphingosine kinase-1 pathway, and is effectively inhibited by GW4869. (PMID:26855418)
• ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-alpha, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity. (PMID:27013100)
• Overexpression of Smpd3 induced cytodifferentiation of HPDL cells, which could be suppressed by an inhibitor of its protein product, nSMase2. In addition,Smpd3 harboring a SNP (rs145616324) showed no activity and failed to induce cytodifferentiation of HPDL cells. Together, these findings suggest that Smpd3 plays an important role in the osteoblastic differentiation of HPDL cells. (PMID:28221099)
• the DK switch regulates ceramide generation by nSMase2 and is governed by an allosteric interdomain interaction at the membrane interface (PMID:28652336)
• The enzymes involved in sphingolipid metabolism are expressed abnormally in B cells from SLE patients. TLR signaling induced the abnormal expression of sphingomyelin phosphodiesterase 3 (SMPD3). TLR signaling also induced the transport of SMPD3 from the Golgi apparatus. Furthermore, the dysfunction of SMPD3 enhanced TLR-induced inflammatory response of B cells and macrophages in turn. (PMID:28889482)
• REVIEW: studies adressing the role of NSM2 in T cell polarity in which the enzyme plays a major role in regulating cytoskeletal dynamics. (PMID:29337691)
• These findings identify neutral sphingomyelinase 2 as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components (PMID:29720981)
• Compounds against human nSMase2 we identified. (PMID:30531925)
• demonstrate that PS binding at the N-terminal and juxtamembrane regions of nSMase2 rather acts as a conformational switch leading to interdomain interactions that are critical to enzyme activation (PMID:30890560)
• Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy. (PMID:33727246)
• Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis. (PMID:33938457)
• Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects. (PMID:34584229)
• Activation of neutral sphingomyelinase 2 through hyperglycemia contributes to endothelial apoptosis via vesicle-bound intercellular transfer of ceramides. (PMID:34951654)
• Inhibition of Neutral Sphingomyelinase 2 by Novel Small Molecule Inhibitors Results in Decreased Release of Extracellular Vesicles by Vascular Smooth Muscle Cells and Attenuated Calcification. (PMID:36768348)
• Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes. (PMID:37640282)
• The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells. (PMID:38542220)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	smpd3	ENSDARG00000098226
mus_musculus	Smpd3	ENSMUSG00000031906
rattus_norvegicus	Smpd3	ENSRNOG00000000257

Protein

Protein identifiers

Sphingomyelin phosphodiesterase 3 — Q9NY59 (reviewed: Q9NY59)

Alternative names: Neutral sphingomyelinase 2, Neutral sphingomyelinase II

All UniProt accessions (4): Q9NY59, H3BS51, H3BTM0, I3L228

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of sphingomyelin to form ceramide and phosphocholine. Ceramide mediates numerous cellular functions, such as apoptosis and growth arrest, and is capable of regulating these 2 cellular events independently. Also hydrolyzes sphingosylphosphocholine. Regulates the cell cycle by acting as a growth suppressor in confluent cells. Probably acts as a regulator of postnatal development and participates in bone and dentin mineralization. Binds to anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) that modulate enzymatic activity and subcellular location. May be involved in IL-1-beta-induced JNK activation in hepatocytes. May act as a mediator in transcriptional regulation of NOS2/iNOS via the NF-kappa-B activation under inflammatory conditions.

Subcellular location. Golgi apparatus membrane. Cell membrane.

Tissue specificity. Predominantly expressed in brain.

Post-translational modifications. Palmitoylated, palmitoylation-deficient proteins are targeted for lysosomal degradation.

Activity regulation. Inhibited by nSMase inhibitor GW4869. Binding of anionic phospholipids (APLs) such as phosphatidylserine (PS) and phosphatidic acid (PA) increases enzymatic activity.

Pathway. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the neutral sphingomyelinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NY59-1	1	yes
Q9NY59-2	2

RefSeq proteins (1): NP_061137* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR017766	Sphingomyelinase/PLipase_C	Family
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR038772	Sph/SMPD2-like	Family

Pfam: PF03372

Enzyme classification (BRENDA):

• EC 3.1.4.12 — sphingomyelin phosphodiesterase (BRENDA: 30 organisms, 220 substrates, 319 inhibitors, 54 Km, 10 kcat entries)

Substrate kinetics (BRENDA)

18 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
SPHINGOMYELIN	0.0006–13	30
2-N-HEXADECANOYLAMINO-4-NITROPHENYLPHOSPHORYLCHO	0.034–0.34	2
4-(4-NITROPHENOXY)-2-HYDROXY-BUTYL-1-PHOSPHORYLC	12.6–39.6	2
1-ALKYL-LYSO-PLATELET ACTIVATING FACTOR	0.048	1
2-(N-HEXADECANOYLAMINO)-4-NITROPHENYLPHOSPHORYLC	1.7	1
2N-HEXADECANOYLAMINO-4-NITROPHENYLPHOSPHORYLCHOL	0.027	1
4-NITROPHENYL PHOSPHORYLCHOLINE	11.6	1
ADP	0.306	1
ADP-RIBOSE	0.348	1
ATP	0.327	1
BIS-P-NITROPHENYL PHOSPHATE	14.5	1
BODIPYFL-C12-SPHINGOMYELIN	0.06	1
CDP-CHOLINE	0.262	1
CDP-ETHANOLAMINE	0.391	1
HEXADECANOYL-P-NITROPHENYL PHOSPHORYLCHOLINE	0.174	1

Catalyzed reactions (Rhea), 8 shown:

• a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4-enine + H(+) (RHEA:19253)
• 1-O-octadecyl-sn-glycero-3-phosphocholine + H2O = 1-O-octadecyl-sn-glycerol + phosphocholine + H(+) (RHEA:39923)
• 1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycerol + phosphocholine + H(+) (RHEA:41119)
• a sphingosylphosphocholine + H2O = a sphingoid base + phosphocholine + H(+) (RHEA:45296)
• an N-(acyl)-sphingosylphosphocholine + H2O = an N-acyl-sphingoid base + phosphocholine + H(+) (RHEA:45300)
• N-(15Z-tetracosenoyl)sphing-4-enine-1-phosphocholine + H2O = N-(15Z-tetracosenoyl)-sphing-4-enine + phosphocholine + H(+) (RHEA:45320)
• N-(tetracosanoyl)-sphing-4-enine-1-phosphocholine + H2O = N-tetracosanoyl-sphing-4-enine + phosphocholine + H(+) (RHEA:45324)
• N-(hexadecanoyl)-sphing-4-enine-1-phosphocholine + H2O = N-hexadecanoylsphing-4-enine + phosphocholine + H(+) (RHEA:45644)

UniProt features (49 total): strand 14, helix 11, lipid moiety-binding region 5, topological domain 3, turn 3, compositionally biased region 3, modified residue 2, intramembrane region 2, chain 1, active site 1, binding site 1, site 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5UVG	X-RAY DIFFRACTION	1.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY59-F1	76.78	0.57

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 (2): 639 (proton acceptor); 512 (important for substrate recognition)

Ligand- & substrate-binding residues (1): 364

Post-translational modifications (7): 178, 291, 53, 54, 59, 397, 398

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5626978	TNFR1-mediated ceramide production
R-HSA-9840310	Glycosphingolipid catabolism

MSigDB gene sets: 383 (showing top): GOBP_PLATELET_DERIVED_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, TGGTGCT_MIR29A_MIR29B_MIR29C, CREL_01, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, chr16q22, GOBP_CARTILAGE_DEVELOPMENT, GOBP_VESICLE_LOCALIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT

GO Biological Process (46): endochondral ossification (GO:0001958), hematopoietic progenitor cell differentiation (GO:0002244), regulation of leukocyte migration (GO:0002685), chondrocyte development involved in endochondral bone morphogenesis (GO:0003433), ceramide metabolic process (GO:0006672), sphingomyelin metabolic process (GO:0006684), sphingomyelin catabolic process (GO:0006685), polysaccharide transport (GO:0015774), peptide hormone secretion (GO:0030072), bone mineralization (GO:0030282), BMP signaling pathway (GO:0030509), collagen metabolic process (GO:0032963), multicellular organism growth (GO:0035264), positive regulation of mitotic nuclear division (GO:0045840), platelet-derived growth factor receptor signaling pathway (GO:0048008), lung alveolus development (GO:0048286), positive regulation of smooth muscle cell proliferation (GO:0048661), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), regulation of cartilage development (GO:0061035), cellular response to hydrogen peroxide (GO:0070301), G1 to G0 transition (GO:0070314), cellular response to magnesium ion (GO:0071286), cellular response to tumor necrosis factor (GO:0071356), cellular response to redox state (GO:0071461), DNA biosynthetic process (GO:0071897), extracellular matrix assembly (GO:0085029), sphingolipid mediated signaling pathway (GO:0090520), dentinogenesis (GO:0097187), bone growth (GO:0098868), mitotic nuclear division (GO:0140014), cellular response to oxidised low-density lipoprotein particle stimulus (GO:0140052), negative regulation of hyaluronan biosynthetic process (GO:1900126), cellular response to peptide (GO:1901653), positive regulation of exosomal secretion (GO:1903543), skeletal system development (GO:0001501), ossification (GO:0001503), chondrocyte development (GO:0002063), lipid metabolic process (GO:0006629), sphingolipid metabolic process (GO:0006665), signal transduction (GO:0007165)

GO Molecular Function (10): phosphatidylserine binding (GO:0001786), sphingomyelin phosphodiesterase activity (GO:0004767), phosphoric diester hydrolase activity (GO:0008081), identical protein binding (GO:0042802), metal ion binding (GO:0046872), neutral sphingomyelin phosphodiesterase activity (GO:0061751), phosphatidic acid binding (GO:0070300), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): Golgi cis cisterna (GO:0000137), Golgi membrane (GO:0000139), extracellular region (GO:0005576), cytoplasm (GO:0005737), plasma membrane (GO:0005886), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNF signaling	1
Glycosphingolipid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
endochondral bone morphogenesis	2
sphingolipid metabolic process	2
phospholipid binding	2
anion binding	2
replacement ossification	1
hemopoiesis	1
cell differentiation	1
regulation of immune system process	1
regulation of cell migration	1
leukocyte migration	1
chondrocyte development	1
chondrocyte differentiation involved in endochondral bone morphogenesis	1
phospholipid metabolic process	1
sphingomyelin metabolic process	1
phospholipid catabolic process	1
sphingolipid catabolic process	1
carbohydrate transport	1
polysaccharide localization	1
peptide secretion	1
hormone secretion	1
nitrogen compound transport	1
ossification	1
biomineral tissue development	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
metabolic process	1
multicellular organismal process	1
developmental growth	1
regulation of mitotic nuclear division	1
positive regulation of nuclear division	1
positive regulation of cell cycle process	1
mitotic nuclear division	1
cell surface receptor protein tyrosine kinase signaling pathway	1
lung development	1
anatomical structure development	1
positive regulation of cell population proliferation	1
smooth muscle cell proliferation	1
regulation of smooth muscle cell proliferation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMPD3	SMPD2	O60906	983
SMPD3	SMPD4	Q9NXE4	969
SMPD3	SMPD1	P17405	903
SMPD3	RAB27A	P51159	659
SMPD3	CD63	P08962	621
SMPD3	TSG101	Q99816	584
SMPD3	SPTLC2	O15270	574
SMPD3	CD81	P18582	574
SMPD3	RAB27B	O00194	572
SMPD3	CD9	P21926	571
SMPD3	SGMS2	Q8NHU3	563
SMPD3	SPTLC1	O15269	561
SMPD3	SPARC	P09486	557
SMPD3	ASAH1	Q13510	553
SMPD3	CERS2	Q96G23	537

IntAct

26 interactions, top by confidence:

A	B	Type	Score
SMPD3	ENDOD1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
PWWP3A	SMC6	psi-mi:“MI:0914”(association)	0.530
SMPD3	EED	psi-mi:“MI:0915”(physical association)	0.400
SMPD3	RACK1	psi-mi:“MI:0915”(physical association)	0.400
TNF	EED	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
GABPA	A2ML1	psi-mi:“MI:0914”(association)	0.350
ST7	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
DSCR9	SMPD3	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	MED31	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	COPS6	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	CRMP1	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	RBM48	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	XRCC6	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	GDF9	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	PLEKHM1	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	RIF1	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	SETDB1	psi-mi:“MI:0915”(physical association)	0.000
SMPD3	VOPP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): CAV1 (Affinity Capture-MS), ENDOD1 (Affinity Capture-MS), STOM (Affinity Capture-MS), TMEM135 (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS), PPP3CA (Affinity Capture-MS), APOB (Affinity Capture-MS), EED (Two-hybrid), SMPD3 (Two-hybrid), EED (Co-localization), SMPD3 (Co-fractionation), EED (Affinity Capture-Western), SMPD3 (Affinity Capture-Western)

ESM2 similar proteins: A3KGK3, A6H603, A9ULG4, B1H1N7, B5DFG1, B6CZ46, D6MZJ6, E9QAM5, F1QG30, O35049, O60906, O70572, O75064, O95382, O95398, P10937, P70261, Q149M9, Q1LXZ7, Q2KHV9, Q2KJ28, Q32NB8, Q3U1Y4, Q5R8K7, Q5XIL6, Q5ZHN9, Q68DD2, Q6NVG1, Q6ZNJ1, Q6ZPS2, Q6ZQA0, Q76MJ5, Q7TMC8, Q80YU0, Q8BHF7, Q8N0W3, Q91X21, Q95KI5, Q99MQ3, Q9BXM7

Diamond homologs: D6MZJ6, F1QG30, O35049, Q9JJY3, Q9NY59, Q86IG2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	101
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2368 predictions. Top by Δscore:

Variant	Effect	Δscore
16:68361313:G:GC	acceptor_gain	1.0000
16:68363494:A:AC	donor_gain	1.0000
16:68363495:C:CC	donor_gain	1.0000
16:68363495:CTT:C	donor_gain	1.0000
16:68363497:T:TA	donor_gain	1.0000
16:68364745:CCTCA:C	donor_loss	1.0000
16:68364746:CTCA:C	donor_loss	1.0000
16:68364748:CA:C	donor_loss	1.0000
16:68364749:A:AC	donor_gain	1.0000
16:68364749:A:AG	donor_loss	1.0000
16:68364750:C:CC	donor_gain	1.0000
16:68364750:CC:C	donor_loss	1.0000
16:68364902:GTCCT:G	acceptor_gain	1.0000
16:68364903:TCCT:T	acceptor_gain	1.0000
16:68364904:CCTC:C	acceptor_gain	1.0000
16:68364905:CT:C	acceptor_gain	1.0000
16:68364906:TC:T	acceptor_loss	1.0000
16:68364907:C:CC	acceptor_gain	1.0000
16:68364908:T:A	acceptor_loss	1.0000
16:68364915:C:CT	acceptor_gain	1.0000
16:68448352:CCT:C	donor_gain	1.0000
16:68361305:CTC:C	acceptor_gain	0.9900
16:68361308:C:CA	acceptor_loss	0.9900
16:68361313:G:C	acceptor_gain	0.9900
16:68361317:G:C	acceptor_gain	0.9900
16:68361317:G:GC	acceptor_gain	0.9900
16:68361592:T:TA	donor_gain	0.9900
16:68361601:A:AC	donor_gain	0.9900
16:68361602:C:CC	donor_gain	0.9900
16:68361602:CGG:C	donor_gain	0.9900

AlphaMissense

4265 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:68370949:G:C	S411R	1.000
16:68370949:G:T	S411R	1.000
16:68370951:T:G	S411R	1.000
16:68371676:A:C	I169S	1.000
16:68371676:A:G	I169T	1.000
16:68361656:G:T	R605S	0.999
16:68363502:A:G	L568P	0.999
16:68365052:C:T	G455E	0.999
16:68365053:C:A	G455W	0.999
16:68371676:A:T	I169N	0.999
16:68371682:A:C	I167S	0.999
16:68371682:A:G	I167T	0.999
16:68363777:C:G	G549R	0.998
16:68370953:G:T	A410D	0.998
16:68371633:G:C	S183R	0.998
16:68371633:G:T	S183R	0.998
16:68371635:T:G	S183R	0.998
16:68371661:G:T	P174H	0.998
16:68371670:A:T	I171N	0.998
16:68361247:C:G	A643P	0.997
16:68361655:C:G	R605P	0.997
16:68361754:A:G	L572P	0.997
16:68363559:C:T	G549D	0.997
16:68364761:G:C	N515K	0.997
16:68364761:G:T	N515K	0.997
16:68364780:C:T	G509E	0.997
16:68364795:A:G	F504S	0.997
16:68364879:A:G	L476P	0.997
16:68365053:C:G	G455R	0.997
16:68365053:C:T	G455R	0.997

dbSNP variants (sampled 300 via entrez): RS1000003195 (16:68396382 A>G), RS1000015622 (16:68380201 T>A), RS1000036009 (16:68402803 A>T), RS1000103101 (16:68416298 T>C,G), RS1000154444 (16:68448362 CG>C), RS1000169961 (16:68434209 A>T), RS1000178818 (16:68444047 A>G), RS1000228443 (16:68429705 CT>C), RS1000231061 (16:68444354 G>A), RS1000233064 (16:68386189 T>A,C), RS1000241326 (16:68398424 T>A,C), RS1000246639 (16:68386616 G>A), RS1000257227 (16:68392403 G>A), RS1000289537 (16:68422543 C>T), RS1000289546 (16:68361399 G>A)

Disease associations

OMIM: gene MIM:605777 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST008362_60	Birth weight	7.000000e-06
GCST008362_61	Birth weight	1.000000e-08
GCST008363_126	Offspring birth weight	8.000000e-08
GCST008595_208	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	6.000000e-11
GCST008839_327	Height	1.000000e-18
GCST010002_113	Refractive error	2.000000e-14
GCST010083_28	Hemoglobin levels	1.000000e-10
GCST012232_25	Lipoprotein (a) levels	3.000000e-12
GCST90016585_24	Chronic obstructive pulmonary disease x ever smoker interaction (2df)	4.000000e-09
GCST90016588_11	Chronic obstructive pulmonary disease in ever smokers	6.000000e-07
GCST90016590_27	Chronic obstructive pulmonary disease x current smoker interaction (2df)	1.000000e-08
GCST90016591_25	Chronic obstructive pulmonary disease x current smoker interaction (main effect)	1.000000e-06
GCST90016594_46	Chronic obstructive pulmonary disease in non-current smokers	2.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004509	hemoglobin measurement
EFO:0006925	lipoprotein A measurement
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523470 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,850 (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
CHEMBL3889654	LAROTRECTINIB	4	1,850

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Sphingomyelin phosphodiesterase

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[(3R)-1-[3-(1H-indol-6-yl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]acetamide	IC50	700 nM	US-11427590: Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) for the treatment of neurodegenerative diseases

ChEMBL bioactivities

189 potent at pChembl≥5 of 196 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10	nM	CHEMBL4471834
7.70	IC50	20	nM	CHEMBL4449307
7.70	IC50	20	nM	CHEMBL4551018
7.70	IC50	20	nM	CHEMBL4467223
7.70	IC50	20	nM	CHEMBL4449305
7.70	IC50	20	nM	CHEMBL587104
7.52	IC50	30	nM	CHEMBL1342201
7.40	IC50	40	nM	CHEMBL4458407
7.40	IC50	40	nM	CHEMBL4565746
7.30	IC50	50	nM	CHEMBL4647644
7.30	IC50	50	nM	CHEMBL6027267
7.22	IC50	60	nM	CHEMBL4468906
7.22	IC50	60	nM	CHEMBL5632079
7.16	IC50	70	nM	CHEMBL4471548
7.16	IC50	70	nM	CHEMBL4588691
7.16	IC50	70	nM	CHEMBL4577390
7.16	IC50	70	nM	CHEMBL4533205
7.16	IC50	70	nM	CHEMBL4647644
7.16	IC50	70	nM	CHEMBL5631773
7.05	IC50	90	nM	CHEMBL4514045
7.05	IC50	90	nM	CHEMBL4634085
7.00	IC50	100	nM	CHEMBL4643888
7.00	IC50	100	nM	CHEMBL4635335
7.00	IC50	100	nM	CHEMBL4644091
7.00	IC50	100	nM	CHEMBL4635273
7.00	IC50	100	nM	CHEMBL5771016
6.96	IC50	110	nM	CHEMBL5632974
6.96	IC50	110	nM	CHEMBL5632333
6.92	IC50	120	nM	CHEMBL4573101
6.92	IC50	120	nM	CHEMBL4540577
6.89	IC50	130	nM	CHEMBL4436316
6.89	IC50	130	nM	CHEMBL5633053
6.85	IC50	140	nM	CHEMBL5633524
6.77	IC50	170	nM	CHEMBL5632514
6.72	IC50	190	nM	CHEMBL5632986
6.70	IC50	200	nM	CHEMBL4648675
6.70	IC50	200	nM	CHEMBL4632464
6.70	IC50	200	nM	CHEMBL4633254
6.70	IC50	200	nM	CHEMBL4632713
6.70	IC50	200	nM	CHEMBL4648184
6.70	IC50	200	nM	CHEMBL4632415
6.70	IC50	200	nM	CHEMBL4640034
6.70	IC50	200	nM	CHEMBL4644595
6.68	IC50	210	nM	CHEMBL5633924
6.66	IC50	220	nM	CHEMBL4441694
6.55	IC50	280	nM	CHEMBL5631475
6.52	IC50	300	nM	CHEMBL4643164
6.52	IC50	300	nM	CHEMBL4647138
6.52	IC50	300	nM	CHEMBL4647717
6.52	IC50	300	nM	CHEMBL4639494

PubChem BioAssay actives

125 with measured affinity, of 150 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
2,6-diethoxy-4-(4-phenyl-5-thiophen-2-yl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0100	uM
4-(4,5-diphenyl-1H-imidazol-2-yl)-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0200	uM
4-(4,5-dithiophen-2-yl-1H-imidazol-2-yl)-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0200	uM
2,6-dimethoxy-4-(5-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0200	uM
2,6-dimethoxy-4-(5-methyl-4-phenyl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0200	uM
4-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-yl]-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0200	uM
2,6-dimethoxy-4-(4-phenyl-5-thiophen-2-yl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0300	uM
4-[4,5-bis(furan-2-yl)-1H-imidazol-2-yl]-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0400	uM
4-(4-phenyl-5-thiophen-2-yl-1H-imidazol-2-yl)-2,6-di(propan-2-yloxy)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0400	uM
4-(4-butyl-5-methyl-1H-imidazol-2-yl)-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0600	uM
5-(3-azabicyclo[3.1.1]heptan-3-yl)-N,N-dimethylpyrazolo[1,5-a]pyrimidin-3-amine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.0600	uM
3-(3,4-dimethoxyphenyl)-2,6-dimethyl-8-pyrrolidin-1-ylimidazo[1,2-b]pyridazine	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.0700	uM
4-[4,5-bis(4-methylphenyl)-1H-imidazol-2-yl]-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0700	uM
4-(4-phenyl-5-thiophen-2-yl-1H-imidazol-2-yl)-2,6-bis(2,2,2-trifluoroethoxy)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0700	uM
2,6-dimethoxy-4-(4-phenyl-5-propan-2-yl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0700	uM
2,6-dimethoxy-4-(5-phenyl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0700	uM
N,N-dimethyl-5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidin-3-amine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.0700	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]-4-methylbenzenesulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.0900	uM
4-[4,5-di(propan-2-yl)-1H-imidazol-2-yl]-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.0900	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]-2,2-difluoro-2-phenylacetamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.1000	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]cyclopropanesulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.1000	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]thiophene-2-sulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.1000	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]hexanamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.1000	uM
N,N-dimethyl-5-piperidin-1-ylpyrazolo[1,5-a]pyrimidin-3-amine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.1100	uM
5-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-N,N-dimethylpyrazolo[1,5-a]pyrimidin-3-amine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.1100	uM
4-(4,5-diethyl-1H-imidazol-2-yl)-2,6-dimethoxyphenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.1200	uM
2,6-dicyclopentyloxy-4-(4-phenyl-5-thiophen-2-yl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.1200	uM
2,6-dimethoxy-4-[5-(4-methylphenyl)-1H-imidazol-2-yl]phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.1300	uM
N,N-dimethyl-5-morpholin-4-ylpyrazolo[1,5-a]pyrimidin-3-amine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.1300	uM
(3R)-1-[3-(dimethylamino)pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-3-ol	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.1400	uM
N,N-dimethyl-5-(3-phenylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.1700	uM
1-[3-(dimethylamino)pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-4-ol	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.1900	uM
(3-methylphenyl) N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]carbamate	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]-4-(trifluoromethyl)benzenesulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
4-cyano-N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]benzenesulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
4-acetyl-N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]benzenesulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
N-[(3R)-1-[2,6-dimethyl-3-[4-(trifluoromethoxy)phenyl]imidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]acetamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
N-[(3R)-1-[2,6-dimethyl-3-(4-methylsulfanylphenyl)imidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]acetamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]-2-phenoxyacetamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
1-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]-3-phenylurea	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.2000	uM
3-N,3-N,5-N,5-N-tetramethylpyrazolo[1,5-a]pyrimidine-3,5-diamine	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.2100	uM
2,6-dimethoxy-4-(5-methyl-1H-imidazol-2-yl)phenol	1587316: Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	ic50	0.2200	uM
(3S)-1-(3-aminopyrazolo[1,5-a]pyrimidin-5-yl)piperidin-3-ol	2137580: Inhibition of recombinant human nSMase2 using SM as substrate incubated for 1 hr by fluorescence assay	ic50	0.2800	uM
cyclohexyl N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]carbamate	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM
benzyl N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]carbamate	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM
N-[(3R)-1-(2,6-dimethyl-3-thiophen-2-ylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl]acetamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM
phenyl N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]carbamate	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM
naphthalen-2-yl N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]carbamate	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM
N-[(3R)-1-[3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl]pyrrolidin-3-yl]propane-2-sulfonamide	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM
3-(3,4-dimethoxyphenyl)-2,6-dimethyl-8-[(3R)-3-(sulfamoylamino)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine	1654752: Inhibition of human recombinant full-length nSMase expressed in HEK293 cells using sphingomyelin as substrate measured after 1 hr by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection-coupled amplex reagent based fluorescence assay	ic50	0.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
(+)-JQ1 compound	increases expression	2
Hydrogen Peroxide	affects expression, increases activity	2
N-Nitrosopyrrolidine	decreases expression	2
Aflatoxin B1	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
OTX015	increases expression	1
mivebresib	increases expression	1
sotorasib	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
sodium arsenate	increases abundance, decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
mithramycin A	decreases expression	1
clothianidin	decreases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4385861	Binding	Inhibition of human recombinant nSMase expressed in HEK293 cells using sphingomyelin as substrate by alkaline phosphatase, choline oxidase and horseradish peroxidase dependent H2O2 detection based fluorescence coupled assay	Neutral sphingomyelinase 2 inhibitors based on the 4-(1H-imidazol-2-yl)-2,6-dialkoxyphenol scaffold. — Eur J Med Chem

Clinical trials (associated diseases)

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