ENPP2

Summary

ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, HGNC:3357) is a protein-coding gene on chromosome 8q24.12, encoding Autotaxin (Q13822). Secreted lysophospholipase D that hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids.

The protein encoded by this gene functions as both a phosphodiesterase, which cleaves phosphodiester bonds at the 5’ end of oligonucleotides, and a phospholipase, which catalyzes production of lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells and has angiogenic properties, and its expression is upregulated in several kinds of carcinomas. The gene product is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 5168 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 164 total — 2 pathogenic
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001040092

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3357
Approved symbol	ENPP2
Name	ectonucleotide pyrophosphatase/phosphodiesterase 2
Location	8q24.12
Locus type	gene with protein product
Status	Approved
Aliases	ATX, PD-IALPHA
Ensembl gene	ENSG00000136960
Ensembl biotype	protein_coding
OMIM	601060
Entrez	5168

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000075322, ENST00000259486, ENST00000427067, ENST00000518109, ENST00000518958, ENST00000520066, ENST00000522167, ENST00000522826, ENST00000523861, ENST00000874336, ENST00000874337, ENST00000874338, ENST00000874339, ENST00000874340, ENST00000874341, ENST00000874342, ENST00000962639, ENST00000962640

RefSeq mRNA: 4 — MANE Select: NM_001040092 NM_001040092, NM_001130863, NM_001330600, NM_006209

CCDS: CCDS34936, CCDS47914, CCDS6329, CCDS83317

Canonical transcript exons

ENST00000075322 — 25 exons

Exon	Start	End
ENSE00001022664	119580116	119580167
ENSE00001022665	119583962	119584049
ENSE00001022669	119570705	119570841
ENSE00001022672	119587044	119587075
ENSE00001022673	119607922	119607977
ENSE00001022674	119601397	119601462
ENSE00001022675	119616265	119616384
ENSE00001022677	119586186	119586313
ENSE00001022678	119593752	119593860
ENSE00001022682	119582418	119582602
ENSE00001022683	119600678	119600750
ENSE00001022685	119619244	119619304
ENSE00001090688	119638425	119638527
ENSE00001158678	119621394	119621519
ENSE00001158688	119626565	119626720
ENSE00001279359	119583717	119583804
ENSE00001351616	119638748	119638839
ENSE00003503446	119617164	119617243
ENSE00003533656	119569235	119569370
ENSE00003617704	119590505	119590630
ENSE00003627176	119562857	119563013
ENSE00003647725	119568175	119568252
ENSE00003663036	119617466	119617563
ENSE00003680629	119564823	119564955
ENSE00003899050	119557086	119557691

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.9700 / max 1115.9047, expressed in 1139 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94619	21.1953	1115
94623	10.8580	402
94622	0.8100	148
94624	0.0943	35
94611	0.0124	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.97	gold quality
choroid plexus epithelium	UBERON:0003911	99.96	gold quality
retina	UBERON:0000966	99.94	gold quality
inferior vagus X ganglion	UBERON:0005363	99.90	gold quality
corpus callosum	UBERON:0002336	99.82	gold quality
endothelial cell	CL:0000115	99.78	gold quality
pons	UBERON:0000988	99.74	gold quality
subthalamic nucleus	UBERON:0001906	99.74	gold quality
superior vestibular nucleus	UBERON:0007227	99.72	gold quality
middle frontal gyrus	UBERON:0002702	99.67	gold quality
lateral globus pallidus	UBERON:0002476	99.65	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.62	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.59	gold quality
medulla oblongata	UBERON:0001896	99.56	gold quality
ventral tegmental area	UBERON:0002691	99.53	gold quality
substantia nigra pars compacta	UBERON:0001965	99.28	gold quality
cranial nerve II	UBERON:0000941	99.26	gold quality
tibia	UBERON:0000979	99.21	gold quality
globus pallidus	UBERON:0001875	99.16	gold quality
spinal cord	UBERON:0002240	99.14	gold quality
decidua	UBERON:0002450	99.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.07	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.03	gold quality
medial globus pallidus	UBERON:0002477	99.02	gold quality
inferior olivary complex	UBERON:0002127	98.92	gold quality
visceral pleura	UBERON:0002401	98.81	gold quality
periodontal ligament	UBERON:0008266	98.80	gold quality
placenta	UBERON:0001987	98.75	gold quality
CA1 field of hippocampus	UBERON:0003881	98.70	gold quality
pylorus	UBERON:0001166	98.69	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	2197.91
E-GEOD-100618	yes	877.86
E-MTAB-10287	yes	93.35
E-HCAD-35	yes	91.91
E-MTAB-6701	yes	70.84
E-HCAD-25	yes	65.27
E-MTAB-5061	yes	25.58
E-GEOD-135922	yes	18.75
E-GEOD-84465	yes	14.17
E-GEOD-81547	yes	13.19
E-MTAB-6678	yes	13.18
E-GEOD-83139	yes	9.00
E-CURD-112	yes	8.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CTNNB1, FOXC1, JUN, MYCN, NFAT5, NFATC2, NFKB2, RELB, STAT3

miRNA regulators (miRDB)

75 targeting ENPP2, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-8063	99.91	69.76	3146

Literature-anchored findings (GeneRIF, showing 40)

• human plasma lysophospholipase D may play a role in induction of parturition (PMID:12176993)
• our results suggest that the expression of ATX is closely linked to the invasiveness of breast cancer cells. (PMID:12498389)
• high expression of autotaxin is associated with undifferentiated anaplastic thyroid carcinoma, increased cell motility and proliferation (PMID:15027116)
• Up-regulation of adipocyte autotaxin expression, which could be related to the severe type 2 diabetes phenotype and adipocyte insulin resistance. (PMID:15700135)
• S1P is an inhibitor of ATX, as well as a receptor ligand (PMID:15769751)
• alpha6beta4 integrin potentiates autotaxin expression through the upregulation and activation of NFAT1. (PMID:15897878)
• results identify the induction of autotaxin and the subsequent generation of lysophosphatidic acid as key molecular events that mediate the EBV-induced growth and survival of Hodgkin lymphoma cells (PMID:15933052)
• Expression of LPLD autotaxin (ATX) is greatly increased in blister skin when compared with normal skin. (PMID:16117781)
• This study thus provides the first evidence that CST6 plays a role in the modulation of genes, particularly, genes that are highly relevant to breast cancer progression. (PMID:16356477)
• Expression of the autotaxin gene and cell signaling by lysophosphatidic acid may be involved in the pathology of ATD, and that this cell signaling pathway may be a potential target of treatments for ATD. (PMID:16529861)
• the autocrine production of LPA by cancer cell-derived ATX and exogenously supplied LPC contribute to the invasiveness of cancer cells (PMID:16627485)
• ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Galpha13 knockout phenotype. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. (PMID:16782887)
• These results indicate that the generation of cyclic phosphatidic acid and lysophosphatidic acid in serum is mainly attributed to autotaxin. (PMID:16837466)
• autotaxin induces uPA expression via the Gi-PI3K-Akt-NF-kappaB signaling pathway that might be critical for autotaxin-induced tumor cell invasion and metastasis (PMID:17013094)
• Serum ATX activity is increased in chronic hepatitis C in association with liver fibrosis (PMID:17577119)
• Enpp2 is a candidate gene controlling lung function development in mice. (PMID:17804602)
• Patients with hepatitis C and hepatocellular carcinoma show differential expression of various components of the autotaxin pathway versus normal patients. (PMID:17902023)
• Together, our results show that in epithelial cells ATX and LPA act as strong stimulators of cell migration by recruiting PLC-gamma 1 and villin, both of which participate in the initiation of protrusion. (PMID:18054784)
• Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. (PMID:18175805)
• Recombinanat human ATX S48 shows lysoPLD enzymatic activity and effectively stimulates the growth and motile activity of the human tumor cells as well as native ATX. (PMID:18249559)
• Facilitates the entry of lymphocytes from the blood into secondary lymphoid organs. (PMID:18327261)
• Positive feedback loop involving VEGFA, autotaxin and lysophosphatidic acid that could affect tumor progression in ovarian cancer cells. (PMID:18337445)
• High levels of ATX is associated with thyroid carcinoma (PMID:18497954)
• LPS induces ATX expression in THP-1 cells via a PKR, JNK and p38 MAPK-mediated mechanism, and the ATX induction is likely to enhance immune cell migration in proinflammatory response by regulating LPA levels in the microenvironment. (PMID:19027716)
• Review discusses ATX expression in adipose tissue, which is significantly upregulated in patients exhibiting both insulin resistance and impaired glucose tolerance or type 2 diabetes associated with massive obesity. (PMID:19204739)
• Knocking down autotaxin secretion, or inhibiting its catalytic activity, blocked cell migration by preventing lysophosphatidate production. (PMID:19204929)
• Autotaxin promotes the expression of matrix metalloproteinase-3 via activation of the MAPK cascade in human fibrosarcoma HT-1080 cells. (PMID:19212832)
• Two novel point mutations near the enzyme active site (H226Q and H434Q) confer attenuated activity toward all substrates tested. (PMID:19222837)
• These results indicate that production of lysophosphatidic acid by lysophospholipase D is elevated in pathological pregnancies, and may play a role in induction and/or progression of systemic vascular dysfunction preterm labor or pre-eclampsia. (PMID:19297419)
• ATX and LPA receptors can contribute to the initiation and progression of breast cancer. (PMID:19477432)
• review of autotxin functions, chemistry, genetics, measurement, pathophysiology, and its potentail as a cancer target [review] (PMID:19506801)
• no significant difference in activity between systemic sclerosis subjects and controls (PMID:19521548)
• Serum ATX activity was found to be enhanced in relation to hepatic fibrosis in chronic liver disease due to hepatitis virus C infection, and ATX might contribute to the pathogenesis of hepatic fibrosis. (review) (PMID:19522250)
• High Expression of autotaxin is associated with development and progression of prostate cancer. (PMID:19549252)
• trophoblasts might produce ATX and its bioactive resultant substance, Lysophosphatidic acid, paralleled with gestational weeks. (PMID:19614625)
• These data show a role for ATX in maintaining expression of receptors required for VEGF and lysophospholipids to accelerate angiogenesis. (PMID:20197381)
• Data show that endothelial cells can be instructed to engage a phospholipase Cgamma-dependent intrinsic destabilization pathway that results in the production of soluble regression factors such as autotaxin and lysophosphatidic acid. (PMID:20231358)
• This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human hepatocellular carcinoma (PMID:20356387)
• This review summarizes the historical aspects, structural basis, pathophysiological functions identified in mice studies and clinical relevance discovered by measuring the blood ATX level in human. (PMID:20495010)
• High autotaxin is associated with colorectal cancer. (PMID:20623382)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	enpp2	ENSDARG00000011257
mus_musculus	Enpp2	ENSMUSG00000022425
rattus_norvegicus	Enpp2	ENSRNOG00000004089
caenorhabditis_elegans		WBGENE00007753
caenorhabditis_elegans		WBGENE00007755
caenorhabditis_elegans		WBGENE00015283

Paralogs (6): ENPP4 (ENSG00000001561), ENPP5 (ENSG00000112796), ENPP3 (ENSG00000154269), ENPP6 (ENSG00000164303), ENPP7 (ENSG00000182156), ENPP1 (ENSG00000197594)

Protein

Protein identifiers

Autotaxin — Q13822 (reviewed: Q13822)

Alternative names: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, Extracellular lysophospholipase D

All UniProt accessions (5): E5RIA2, Q13822, E5RIB9, E5RJ49, E7EUF1

UniProt curated annotations — full annotation on UniProt →

Function. Secreted lysophospholipase D that hydrolyzes lysophospholipids to produce the signaling molecule lysophosphatidic acid (LPA) in extracellular fluids. Its major substrate is lysophosphatidylcholine. Can also act on sphingosylphosphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Required for LPA production in activated platelets, cleaves the sn-1 lysophospholipids to generate sn-1 lysophosphatidic acids containing predominantly 18:2 and 20:4 fatty acids. Shows a preference for the sn-1 to the sn-2 isomer of 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF).

Subcellular location. Secreted.

Tissue specificity. Detected in blood plasma (at protein level). Predominantly expressed in brain, placenta, ovary, and small intestine. Expressed in a number of carcinomas such as hepatocellular and prostate carcinoma, neuroblastoma and non-small-cell lung cancer. Expressed in body fluids such as plasma, cerebral spinal fluid (CSF), saliva, follicular and amniotic fluids. Not detected in leukocytes. Isoform 1 is more highly expressed in peripheral tissues than in the central nervous system (CNS). Adipocytes only express isoform 1. Isoform 3 is more highly expressed in the brain than in peripheral tissues.

Post-translational modifications. N-glycosylation, but not furin-cleavage, plays a critical role on secretion and on lysoPLD activity. The interdomain disulfide bond between Cys-414 and Cys-806 is essential for catalytic activity.

Activity regulation. Inhibited by lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). Inhibited by EDTA and EGTA.

Cofactor. Binds 2 Zn(2+) ions per subunit. Binds 1 Ca(2+) ion per subunit.

Domain organisation. The nuclease-like domain is most probably catalytically inactive as residues that are essential for catalysis in the DNA/RNA non-specific endonucleases are not conserved. However, it is required for the stability of the protein and the catalytic activity born by the Phosphodiesterase domain.

Induction. Up-regulated in massively obese subjects with glucose intolerance, and during adipogenesis.

Similarity. Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13822-1	1, ATXter, Beta	yes
Q13822-2	2, ATXmel, Alpha
Q13822-3	3, Gamma

RefSeq proteins (4): NP_001035181, NP_001124335, NP_001317529, NP_006200 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001212	Somatomedin_B_dom	Domain
IPR001604	Endo_G_ENPP1-like_dom	Domain
IPR002591	Phosphodiest/P_Trfase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR020436	SMB_chordata	Domain
IPR020821	ENPP1-3/EXOG-like_nuc-like	Domain
IPR036024	Somatomedin_B-like_dom_sf	Homologous_superfamily
IPR044925	His-Me_finger_sf	Homologous_superfamily
IPR044929	DNA/RNA_non-sp_Endonuclease_sf	Homologous_superfamily

Pfam: PF01033, PF01223, PF01663

Enzyme classification (BRENDA):

• EC 3.1.4.39 — alkylglycerophosphoethanolamine phosphodiesterase (BRENDA: 14 organisms, 123 substrates, 265 inhibitors, 67 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
LYSOPHOSPHATIDYLCHOLINE	0.094–1	8
FS-3	0.0026–0.019	4
LYSOPHOSPHATIDYLCHOLINE 16:0	0.066–0.126	4
LYSOPHOSPHATIDYLCHOLINE 18:1	0.069–0.126	4
4-NITROPHENYL-TMP	0.7–5.6	3
LYSOPHOSPHATIDYLCHOLINE 18:0	0.089–0.27	3
1-LAUROYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHOCHOLINE	1.9–2.3	2
1-LINOLEOYL-2-HYDROXY-SN-GLYCERO-SN-3-PHOSPHOCHO	0.84–2.4	2
1-MYRISTOYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHOCHOLIN	0.25–0.7	2
1-O-1’-(Z)-OCTADECENYL-2-HYDROXY-SN-GLYCERO-3-PH	0.22–1.3	2
1-O-OCTADECYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHOCHOL	0.16–0.31	2
1-OLEOYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHOCHOLINE	0.28–0.56	2
1-PALMITOYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHOCHOLIN	0.13–0.43	2
1-STEAROYL-2-HYDROXY-SN-GLYCERO-3-PHOSPHOCHOLINE	0.2–0.3	2
1-ALKYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.097	1

Catalyzed reactions (Rhea), 12 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1,2-diacyl-sn-glycero-3-phosphate + choline + H(+) (RHEA:14445)
• a 1-O-alkyl-sn-glycero-3-phosphoethanolamine + H2O = a 1-O-alkyl-sn-glycero-3-phosphate + ethanolamine + H(+) (RHEA:15965)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + H2O = 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + choline + H(+) (RHEA:38915)
• sphing-4-enine-phosphocholine + H2O = sphing-4-enine 1-phosphate + choline + H(+) (RHEA:38919)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine + H2O = 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ethanolamine + H(+) (RHEA:38927)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine + H2O = 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + L-serine + H(+) (RHEA:38931)
• 1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphate + choline + H(+) (RHEA:38975)
• 1-octadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-octadecanoyl-sn-glycero-3-phosphate + choline + H(+) (RHEA:38979)
• 1-tetradecanoyl-sn-glycero-3-phosphocholine + H2O = 1-tetradecanoyl-sn-glycerol 3-phosphate + choline + H(+) (RHEA:38983)
• 1-dodecanoyl-sn-glycero-3-phosphocholine + H2O = 1-dodecanoyl-sn-glycerol 3-phosphate + choline + H(+) (RHEA:38991)
• a 1-acyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphate + choline + H(+) (RHEA:38995)
• a 1-acyl-sn-glycero-3-phospho-L-serine + H2O = a 1-acyl-sn-glycero-3-phosphate + L-serine + H(+) (RHEA:38999)

UniProt features (174 total): helix 45, strand 33, binding site 24, sequence conflict 20, disulfide bond 15, turn 9, mutagenesis site 8, glycosylation site 4, region of interest 3, sequence variant 3, domain 2, splice variant 2, signal peptide 1, propeptide 1, chain 1, site 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4ZG7	X-RAY DIFFRACTION	1.75
4ZG6	X-RAY DIFFRACTION	1.8
8C3P	X-RAY DIFFRACTION	2.38
5MHP	X-RAY DIFFRACTION	2.43
8C3O	X-RAY DIFFRACTION	2.47
5KXA	X-RAY DIFFRACTION	2.59
4ZGA	X-RAY DIFFRACTION	2.6
5M7M	X-RAY DIFFRACTION	2.7
4ZG9	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13822-F1	91.61	0.85

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): 853 (essential for catalytic activity); 210 (nucleophile)

Ligand- & substrate-binding residues (24): 172; 210; 210; 210; 210; 231; 231; 231; 312; 312; 312; 312 …

Disulfide bonds (15): 59–76, 63–94, 74–87, 80–86, 103–120, 108–138, 118–131, 124–130, 149–195, 157–351, 367–469, 414–806, 567–667, 569–652, 775–785

Glycosylation sites (4): 54, 411, 525, 807

Mutagenesis-validated functional residues (8):

Position	Phenotype
170	reduces lysophospholipase activity by about 70%.
210	loss of lysophospholipase activity and ability to hydrolyze sphingosylphosphorylcholine.
211	reduces lysophospholipase activity by about 70%.
218	reduces lysophospholipase activity by about 50%.
231	strongly reduced lysophospholipase activity.
307	reduces lysophospholipase activity by about 70%.
316	loss of ability to hydrolyze sphingosylphosphorylcholine.
360	loss of ability to hydrolyze sphingosylphosphorylcholine.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-199220	Vitamin B5 (pantothenate) metabolism

MSigDB gene sets: 422 (showing top): VALK_AML_WITH_FLT3_ITD, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, FREAC2_01, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, JAEGER_METASTASIS_DN, GOMF_NUCLEASE_ACTIVITY, BOYAULT_LIVER_CANCER_SUBCLASS_G2, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (14): chemotaxis (GO:0006935), immune response (GO:0006955), phospholipid catabolic process (GO:0009395), positive regulation of epithelial cell migration (GO:0010634), sphingolipid catabolic process (GO:0030149), regulation of cell migration (GO:0030334), phosphatidylcholine catabolic process (GO:0034638), positive regulation of lamellipodium morphogenesis (GO:2000394), lipid metabolic process (GO:0006629), phospholipid metabolic process (GO:0006644), lipid catabolic process (GO:0016042), vesicle-mediated transport (GO:0016192), cell motility (GO:0048870), positive regulation of peptidyl-tyrosine phosphorylation (GO:0050731)

GO Molecular Function (11): nucleic acid binding (GO:0003676), phosphodiesterase I activity (GO:0004528), phosphatidylcholine lysophospholipase A1 activity (GO:0004622), D-type glycerophospholipase activity (GO:0004630), scavenger receptor activity (GO:0005044), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), polysaccharide binding (GO:0030247), alkylglycerophosphoethanolamine phosphodiesterase activity (GO:0047391), metal ion binding (GO:0046872)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphoric diester hydrolase activity	3
lipid catabolic process	2
lipid metabolic process	2
cellular process	2
cellular anatomical structure	2
response to chemical	1
taxis	1
immune system process	1
response to stimulus	1
phospholipid metabolic process	1
organophosphate catabolic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
positive regulation of cell migration	1
sphingolipid metabolic process	1
cell migration	1
regulation of cell motility	1
phosphatidylcholine metabolic process	1
glycerophospholipid catabolic process	1
positive regulation of developmental process	1
lamellipodium morphogenesis	1
positive regulation of lamellipodium organization	1
regulation of lamellipodium morphogenesis	1
primary metabolic process	1
organophosphate metabolic process	1
catabolic process	1
transport	1
positive regulation of protein phosphorylation	1
peptidyl-tyrosine phosphorylation	1
regulation of peptidyl-tyrosine phosphorylation	1
binding	1
exonuclease activity	1
lysophospholipase A1 activity	1
glycerophospholipase activity	1
cargo receptor activity	1
metal ion binding	1
transition metal ion binding	1
catalytic activity	1
carbohydrate binding	1
cation binding	1

Protein interactions and networks

STRING

1788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENPP2	GDPD1	Q8N9F7	989
ENPP2	GDPD3	Q7L5L3	988
ENPP2	LPAR1	P78351	881
ENPP2	LPAR2	Q9HBW0	803
ENPP2	LPAR3	Q9UBY5	795
ENPP2	LPAR4	Q99677	764
ENPP2	LPAR6	P43657	735
ENPP2	LPAR5	Q9H1C0	719
ENPP2	PLA2G2A	P14555	645
ENPP2	PLA2G10	O15496	633
ENPP2	PLPP3	O14495	582
ENPP2	POU2F3	Q9UKI9	582
ENPP2	SPNS2	Q8IVW8	557
ENPP2	PLA2G4A	P47712	556
ENPP2	VTN	P01141	553

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ENPP2	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
ENPP2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
HSPB1	ENPP2	psi-mi:“MI:0915”(physical association)	0.370
DYRK1A	ENPP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): ITGB4 (Affinity Capture-Western), LPAR1 (Affinity Capture-Western), ENPP2 (Affinity Capture-Western), ENPP2 (Two-hybrid), HIST1H2BH (Proximity Label-MS), ENPP2 (Two-hybrid), ENPP2 (Two-hybrid), ENPP2 (Cross-Linking-MS (XL-MS)), ENPP2 (Affinity Capture-RNA), ENPP2 (Affinity Capture-RNA)

ESM2 similar proteins: A0A2D0TC04, A1A4K5, A2VDP5, A8K7I4, J3SBP3, J3SEZ3, O14638, P06802, P0DQQ4, P15396, P18563, P18564, P22413, P54793, P97259, P97675, Q08834, Q09328, Q13822, Q14CN2, Q1RPR6, Q29444, Q2TU62, Q32KH8, Q3SZI1, Q4FZV0, Q5FYA8, Q5GF25, Q5R5M5, Q64610, Q6AYF4, Q6DDW2, Q6DYE8, Q6NXH2, Q6PT52, Q6Q473, Q863C4, Q8BTJ4, Q8K1B9, Q8K2I4

Diamond homologs: A0A2D0TC04, A1A4K5, A2VDP5, J3SBP3, J3SEZ3, O14638, O94323, P06802, P0DQQ4, P15396, P22413, P84039, P97675, Q0VA77, Q13822, Q3TIW9, Q566N0, Q5EZ72, Q5R5M5, Q5RAC0, Q64610, Q6AX80, Q6DYE8, Q6UWV6, Q8BTJ4, Q924C3, Q9EQG7, Q9R1E6, Q9UJA9, Q9Y6X5, W8E7D1, P90754, A1YYW7, B0BND0, F1N5C8, P90755, Q58D68, Q5BKW7, Q5RB45, Q6DDP3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	123
Likely benign	4
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1706511	GRCh37/hg19 8q21.2-24.3(chr8:84712253-146295771)x3	Pathogenic
2424480	NC_000008.10:g.(?117859739)(120844804_?)del	Pathogenic

SpliceAI

3910 predictions. Top by Δscore:

Variant	Effect	Δscore
8:119557687:GAGCT:G	acceptor_gain	1.0000
8:119557688:AGCT:A	acceptor_gain	1.0000
8:119557689:GCT:G	acceptor_gain	1.0000
8:119557690:CT:C	acceptor_gain	1.0000
8:119557690:CTC:C	acceptor_gain	1.0000
8:119557690:CTCTG:C	acceptor_loss	1.0000
8:119557691:TC:T	acceptor_loss	1.0000
8:119557691:TCT:T	acceptor_gain	1.0000
8:119557692:C:A	acceptor_loss	1.0000
8:119557692:C:CC	acceptor_gain	1.0000
8:119557692:C:G	acceptor_gain	1.0000
8:119557693:T:A	acceptor_loss	1.0000
8:119557697:A:AC	acceptor_gain	1.0000
8:119557697:A:C	acceptor_gain	1.0000
8:119562850:AACTC:A	donor_loss	1.0000
8:119562851:ACTCA:A	donor_loss	1.0000
8:119562852:CTC:C	donor_loss	1.0000
8:119562853:T:TC	donor_loss	1.0000
8:119562854:CACA:C	donor_loss	1.0000
8:119562855:A:AC	donor_gain	1.0000
8:119562855:A:C	donor_loss	1.0000
8:119562856:C:CC	donor_gain	1.0000
8:119562856:CA:C	donor_gain	1.0000
8:119562856:CATTG:C	donor_gain	1.0000
8:119562867:T:A	donor_gain	1.0000
8:119563009:CGTAC:C	acceptor_gain	1.0000
8:119563011:TAC:T	acceptor_gain	1.0000
8:119563012:AC:A	acceptor_gain	1.0000
8:119563013:CC:C	acceptor_gain	1.0000
8:119563020:C:CT	acceptor_gain	1.0000

AlphaMissense

5721 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:119583990:C:T	G476E	1.000
8:119583991:C:G	G476R	1.000
8:119583991:C:T	G476R	1.000
8:119607974:A:G	W261R	1.000
8:119607974:A:T	W261R	1.000
8:119616280:C:A	W254C	1.000
8:119616280:C:G	W254C	1.000
8:119616282:A:G	W254R	1.000
8:119616282:A:T	W254R	1.000
8:119616349:A:C	N231K	1.000
8:119616349:A:T	N231K	1.000
8:119616384:C:A	G220W	1.000
8:119562924:C:G	C785S	0.999
8:119562925:A:G	C785R	0.999
8:119562925:A:T	C785S	0.999
8:119562953:A:C	C775W	0.999
8:119562955:A:G	C775R	0.999
8:119570731:A:G	W631R	0.999
8:119570731:A:T	W631R	0.999
8:119582570:C:A	G526W	0.999
8:119583965:C:A	M484I	0.999
8:119583965:C:G	M484I	0.999
8:119583965:C:T	M484I	0.999
8:119583990:C:A	G476V	0.999
8:119583992:G:C	H475Q	0.999
8:119583992:G:T	H475Q	0.999
8:119583994:G:C	H475D	0.999
8:119583999:C:T	G473E	0.999
8:119584000:C:G	G473R	0.999
8:119584000:C:T	G473R	0.999

dbSNP variants (sampled 300 via entrez): RS1000074820 (8:119645398 T>C), RS1000085405 (8:119631200 C>T), RS1000085750 (8:119628155 G>A,C), RS1000090933 (8:119587850 C>T), RS1000159907 (8:119589196 G>A), RS1000171082 (8:119673534 G>A,C,T), RS1000206213 (8:119570337 G>A), RS1000279759 (8:119654179 T>C), RS1000282170 (8:119611509 T>G), RS1000308682 (8:119564495 T>A,C), RS1000309420 (8:119653878 C>T), RS1000326233 (8:119604570 A>G), RS1000378555 (8:119604315 A>T), RS1000436513 (8:119638103 C>G), RS1000464935 (8:119634409 G>A,C)

Disease associations

OMIM: gene MIM:601060 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001263_9	Height	6.000000e-06
GCST008163_82	Height	6.000000e-06
GCST008362_181	Birth weight	7.000000e-13
GCST008363_67	Offspring birth weight	2.000000e-06
GCST008839_288	Height	3.000000e-11
GCST010396_161	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-06
GCST010396_170	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06
GCST010396_270	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-07
GCST010703_255	Brain morphology (MOSTest)	7.000000e-14
GCST011616_62	Cortical volume	8.000000e-11
GCST012094_16	Major depressive disorder and major depressive episode treated with electroconvulsive therapy	8.000000e-08
GCST012095_2	Major depressive episode treated with electroconvulsive therapy	2.000000e-08
GCST90000025_372	Appendicular lean mass	4.000000e-44
GCST90000026_33	Appendicular lean mass	4.000000e-20
GCST90000027_13	Appendicular lean mass	7.000000e-29

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0007874	gut microbiome measurement
EFO:0004346	neuroimaging measurement
EFO:0007634	major depressive episode
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3691 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 114,368 (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
CHEMBL1200712	EVANS BLUE	4	24,260
CHEMBL1551	URSODIOL	4	22,553
CHEMBL272427	TAURURSODIOL	4	4,753
CHEMBL465	DRONABINOL	4	62,107
CHEMBL3828074	ZIRITAXESTAT	3	524
CHEMBL3917975	CAMBRITAXESTAT	2	16
CHEMBL4802146	CUDETAXESTAT	2	150
CHEMBL1207607	TETRAPHENYLPORPHINE TETRASULFONIC ACID	1	5

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7832704	ENPP2		0.00	0
rs2249015	ENPP2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — LPA synthesis

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
cambritaxestat	Inhibition	9.0	pIC50
example 1.11 [WO2014139978]	Inhibition	9.0	pIC50
PF-8380	Inhibition	8.77	pIC50
BI-2545	Inhibition	8.66	pIC50
example 2 [WO2013054185]	Inhibition	8.59	pIC50
ziritaxestat	Inhibition	7.82	pKi
example 31 (24) [WO2012005227]	Inhibition	7.57	pIC50
X-165	Inhibition	7.26	pIC50
inhibitor 32 [PMID: 29620892]	Inhibition	7.22	pIC50
BIO-32546	Inhibition	6.3	pIC50

Binding affinities (BindingDB)

1286 measured of 1965 human assays (1965 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[2-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(4-sulfamoylbenzoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
[2-fluoro-4-(trifluoromethyl)phenyl]methyl 2-(4,5,6,7-tetrahydro-2H-benzotriazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
[2-methyl-4-(trifluoromethoxy)phenyl]methyl 2-(4,5,6,7-tetrahydro-2H-benzotriazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
[2-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(2,3,3a,4,5,6,7,7a-octahydro-1H-benzotriazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
[4-(trifluoromethoxy)phenyl]methyl 2-(2,3,3a,4,5,6,7,7a-octahydro-1H-benzotriazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
[2-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
[2-fluoro-4-(trifluoromethoxy)phenyl]methyl 2-[(5R)-2,3,3a,4,5,6,7,7a-octahydro-1H-benzotriazole-5-carbonyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate	IC50	1 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4- [[methyl(tetrahydrofuran- 3- yl)amino]methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-[[methyl(oxetan-3- yl)amino]methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-(morpholino- methyl)phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4- [[methyl(tetrahydropyran- 4- yl)amino]methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-1-[4-(azepan-1- ylmethyl)phenyl]- N-[5-[2- (4-chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-5- oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-[(4-methyl-1- piperidyl)methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-5- oxo-1-[4-(1- piperidylmethyl)phenyl] pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-[[2- methoxyethyl(methyl) amino]methyl]phenyl]-5- oxo-pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
5-[2-(4- chlorophenyl)ethyl]-N-[1- [4-(morpholino- methyl)phenyl]-5-oxo- pyrrolidine-3-yl]- 1,3,4-thiadiazole-2- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyyl) ethyl]isoxazol- 3-yl]-5-oxo-1-[4-(1- piperidylmethyl)phenyl] pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-(2-oxa-7- azaspiro[3.4]octan-7- ylmethyl)phenyl]-5-oxo- pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-(2-oxa-6- azaspiro[3.3]heptan-6- ylmethyl)phenyl]-5-oxo- pyrrolidine-3- carboxamide	IC50	1 nM	US-10138230: Autotaxin inhibitors
(E)-1-[(3aS,8aR)-2-(2H-benzotriazole-5-carbonyl)-1,3,3a,4,5,7,8,8a-octahydropyrrolo[3,4-d]azepin-6-yl]-3-[3-fluoro-4-(trifluoromethoxy)phenyl]prop-2-en-1-one	IC50	1 nM	US-10669268: Bicyclic derivatives
1-[(3aS,6aS)-5-[(5R)-4,5,6,7-tetrahydro-1H-benzotriazole-5-carbonyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl]-2-(4-bromo-2-tert-butylphenoxy)ethanone	IC50	1 nM	US-10669268: Bicyclic derivatives
[6-(4-chloro-phenyl)-pyridin-3-yl]- [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- tetrahydro-1H-benzotriazole-5-carbonyl)- octahydro-cyclobuta[1,2-c;3,4-c’]dipyrrol- 2-yl]-methanone	IC50	1 nM	US-10849881: Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl
(1-cyclopropylmethoxy-isoquinolin-3-yl)- [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- tetrahydro-1H-benzotriazole-5-carbonyl)- octahydro-cyclobuta[1,2-c;3,4-c’]dipyrrol- 2-yl]-methanone	IC50	1 nM	US-10849881: Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl
(4-isopropoxy-naphthalen-2-yl)- [(3aR,3bS,6aR,6bS)-5-((R)-4,5,6,7- tetrahydro-1H-benzotriazole-5-carbonyl)- octahydro-cyclobuta[1,2-c;3,4-c’]dipyrrol- 2-yl]-methanone	IC50	1.3 nM	US-10849881: Octahydro-cyclobuta[1,2-c;3,4-c′]dipyrrol-2-yl
1-[4-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]-2-fluorophenyl]piperazin-1-yl]ethanone	IC50	1.5 nM	US-20260001863: NOVEL PYRIDAZINES
1-[4-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]phenyl]-2,2-dimethylpiperazin-1-yl]ethanone	IC50	1.6 nM	US-20260001863: NOVEL PYRIDAZINES
1-[5-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]phenyl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone	IC50	1.8 nM	US-20260001863: NOVEL PYRIDAZINES
6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]-N-[[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]methyl]pyridazin-3-amine	IC50	1.8 nM	US-20260001863: NOVEL PYRIDAZINES
1-[4-[6-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]-3-pyridinyl]piperazin-1-yl]ethanone	IC50	1.9 nM	US-20260001863: NOVEL PYRIDAZINES
1-[4-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]-3-(trifluoromethyl)phenyl]piperazin-1-yl]ethanone	IC50	1.9 nM	US-20260001863: NOVEL PYRIDAZINES
(3,5-dichlorophenyl)methyl 4-[4-(2H-triazol-4-yl)butanoylamino]piperidine-1-carboxylate	IC50	2 nM	US-9409895: Autotaxin inhibitors
[2-fluoro-4-(trifluoromethoxy)phenyl]methyl 7-(4,5,6,7-tetrahydro-2H-benzotriazole-5-carbonyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate	IC50	2 nM	US-9493486: Diazaspirocycloalkane and azaspirocycloalkane
N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-[(4-methyl-1- piperidyl)methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
N-[5-(2-cyclohexylethyl)- 1,3,4-thiadiazol-2-yl]-1- [4-(1,4-oxazepan-4- ylmethyl)phenyl]-5-oxo- pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
(3S)-1-[4- (morpholinomethyl) phenyl]-5-oxo-N-[5-[2-[4- (trifluoromethyl)phenyl] ethyl]-1,3,4-thiadiazol-2- yl]pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4- (diethylaminomethyl) phenyl]-5-oxo- pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-5- oxo-1-[4-(1- piperidylmethyl)phenyl] pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
N-[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2-yl]-1- [4-[[2- methoxyethyl(methyl) amino]methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
5-[2-(4- chlorophenyl)ethyl]-N-[1- [4-(1,4-oxazepan-4- ylmethyl)phenyl]-5-oxo- pyrrolidin-3-yl]-1,3,4- thiadiazole-2- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
5-[2-(4- chlorophenyl)ethyl]-N- [(3R)-1-[4- (morpholinomethyl) phenyl]-5-oxo- pyrrolidine-3-yl]- 1,3,4-thiadiazole-2- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
5-[2-(4- chlorophenyl)ethyl]-N- [(3R)-1-[4- (morpholinomethyl) phenyl]pyrrolidine-3- yl]-1,3,4- thiadiazole-2- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
5-[2-(4- chlorophenyl)ethyl]-N- [(3R)-5-oxo-1-[4-(1- piperidylmethyl)phenyl] pyrrolidin-3-yl]isoxazole- 3-carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
5-[2-(4- chlorophenyl)ethyl]-N-[5- oxo-1-[4-(1- piperidylmethyl)phenyl] pyrrolidin-3-yl]isoxazole- 3-carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
N-[5-(2-cyclohexylethyl)- 1,3,4-thiadiazol-2-yl]-1- [4- (morpholinomethyl) phenyl]-5-oxo- pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
(3S)-N-[5-[2-(4- chlorophenyl)ethyl] isoxazol-3-yl]-1-[4- [[methyl(tetrahydrofuran- 3- yl)amino]methyl]phenyl]- 5-oxo-pyrrolidine-3- carboxamide	IC50	2 nM	US-10138230: Autotaxin inhibitors
4-[[[5-[2-(4- chlorophenyl)ethyl]- 1,3,4-thiadiazol-2- yl]amino]methyl]-1-[4- (morpholinomethyl) phenyl]pyrrolidin-2-one	IC50	2 nM	US-10138230: Autotaxin inhibitors
(E)-1-(4-((1-Methyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)prop-2-en-1-one	IC50	2 nM	US-10183025: Autotaxin inhibitors
(R,E)-3-(2-((5-Methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)-1-(2-methyl-4-((2-methyloxazol-4-yl)methyl)piperazin-1-yl)prop-2-en-1-one	IC50	2 nM	US-10183025: Autotaxin inhibitors
1-(4-(5-(1H-1,2,3-Triazol-4-yl)pentyl)piperidin-1-yl)-3-(2-((5-methyl-2H-tetrazol-2-yl)methyl)-4-(trifluoromethyl)phenyl)propan-1-one	IC50	2 nM	US-10183025: Autotaxin inhibitors
3,5-Dichlorobenzyl 4-(4-(2-oxo-2,3-dihydrothiazol-5-yl)butanamido)piperidine-1-carboxylate	IC50	2 nM	US-9630945: Autotaxin inhibitors

ChEMBL bioactivities

2827 potent at pChembl≥5 of 2921 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	ZIRITAXESTAT
9.39	IC50	0.41	nM	CHEMBL5183599
9.37	IC50	0.43	nM	CHEMBL4640012
9.15	IC50	0.7	nM	CHEMBL6144436
9.07	IC50	0.86	nM	CHEMBL6174161
9.01	IC50	0.97	nM	CHEMBL6161831
9.00	IC50	1	nM	CHEMBL3828650
9.00	IC50	1	nM	CAMBRITAXESTAT
9.00	IC50	1.01	nM	CHEMBL4647222
9.00	IC50	1	nM	CHEMBL4871014
9.00	IC50	1	nM	CHEMBL5853724
9.00	IC50	1	nM	CHEMBL5742822
9.00	IC50	1	nM	CHEMBL5942504
9.00	IC50	1	nM	CHEMBL5891838
9.00	IC50	1	nM	CHEMBL6045323
9.00	IC50	1	nM	CHEMBL6056368
9.00	IC50	1	nM	CHEMBL5803951
9.00	IC50	1	nM	CHEMBL5886720
9.00	IC50	1	nM	CHEMBL6049689
9.00	IC50	1	nM	CHEMBL5870235
9.00	IC50	1	nM	CHEMBL5979934
9.00	IC50	1	nM	CHEMBL5855323
9.00	IC50	1	nM	CHEMBL6020792
9.00	IC50	1	nM	CHEMBL5759407
9.00	IC50	1	nM	CHEMBL5980087
9.00	IC50	1	nM	CHEMBL5952493
9.00	IC50	1	nM	CHEMBL5938202
9.00	IC50	1	nM	CHEMBL5766179
9.00	IC50	1	nM	CHEMBL5796635
9.00	IC50	1	nM	CHEMBL5786856
9.00	IC50	1	nM	CHEMBL5797542
9.00	IC50	1	nM	CHEMBL5878354
9.00	IC50	1	nM	CHEMBL6042755
9.00	IC50	1	nM	CHEMBL5954220
9.00	IC50	1	nM	CHEMBL5996747
9.00	IC50	1	nM	CHEMBL5994854
9.00	IC50	1	nM	CHEMBL5976986
9.00	IC50	1	nM	CHEMBL5975093
9.00	IC50	1	nM	CHEMBL5929590
9.00	IC50	1	nM	CHEMBL6050079
9.00	IC50	1	nM	CHEMBL5991071
9.00	IC50	1	nM	CHEMBL5897253
9.00	IC50	1	nM	CHEMBL6060137
9.00	IC50	1	nM	CHEMBL5789598
8.97	IC50	1.08	nM	CHEMBL6171688
8.96	IC50	1.1	nM	CHEMBL3186509
8.96	IC50	1.1	nM	CHEMBL5425421
8.91	IC50	1.23	nM	CHEMBL4217352
8.89	IC50	1.3	nM	CHEMBL4217352
8.89	IC50	1.3	nM	ZIRITAXESTAT

PubChem BioAssay actives

1016 with measured affinity, of 2713 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-[[2-ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]-methylamino]-4-(4-fluorophenyl)-1,3-thiazole-5-carbonitrile	1312322: Inhibition of human ATX using FS3 as substrate preincubated for 30 mins followed by substrate addition measured after 30 mins by fluorescence assay	ic50	<0.0001	uM
(3,5-dichlorophenyl)methyl N-[1-ethyl-5-[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-1,3-thiazol-2-yl]indol-3-yl]carbamate	1656153: Inhibition of human ATX pre-incubated for 45 mins before fluorogenic substrate-3 addition and measured every minute for 30 mins by fluorescence based assay	ic50	0.0004	uM
(3,5-dichlorophenyl)methyl N-[1-ethyl-5-[4-(morpholin-4-ylmethyl)-1,3-thiazol-2-yl]indol-3-yl]carbamate	1877071: Inhibition of human ATX using FS-3 as substrate preincubated for 45 mins followed by substrate addition measured every 1 min for 30 mins by fluorescence based microplate reader analysis	ic50	0.0004	uM
N-[(1S)-1-(4-chlorophenyl)ethyl]-3-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanamide	1325587: Inhibition of human recombinant ATX using Rac-1-Palmitoyl-glycero-3-phosphocholine as substrate incubated for 2 hrs using ADHP fluorogenic peroxidase substrate by horseradish peroxidase/choline oxidase-coupled assay	ic50	0.0010	uM
(3,4-difluorophenyl)methyl N-[1-ethyl-5-[4-[(4-hydroxypiperidin-1-yl)methyl]-1,3-thiazol-2-yl]indol-3-yl]carbamate	1656153: Inhibition of human ATX pre-incubated for 45 mins before fluorogenic substrate-3 addition and measured every minute for 30 mins by fluorescence based assay	ic50	0.0010	uM
8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid	1768433: Inhibition of human ATX assessed as reduction in LPA formation using FS-3 as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by FRET assay	ic50	0.0010	uM
[4-(trifluoromethoxy)phenyl]methyl (3aS,6aS)-2-(3-fluoro-4-sulfamoylbenzoyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate	1312315: Inhibition of recombinant human C-terminal His-tagged ATX expressed in HEK293E cells using lysophosphatidylcholine as substrate preincubated with enzyme followed by substrate addition measured after 1 hr by AmplexRed dye based fluorescence assay	ic50	0.0010	uM
(3,5-dichlorophenyl)methyl 4-[3-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)propyl]piperazine-1-carboxylate	1497192: Inhibition of ATX (unknown origin) assessed as decrease in choline release	ic50	0.0011	uM
3-[6-chloro-7-fluoro-2-methyl-1-(1-propylpyrazol-4-yl)indol-3-yl]sulfanyl-2-fluorobenzoic acid	1975197: Inhibition of ATX (unknown origin) using lysoPLD as substrate	ic50	0.0011	uM
[4-[[1-[(3,5-dichlorophenyl)methoxycarbonyl]piperidine-4-carbonyl]amino]phenyl]methylphosphonic acid	1382928: Inhibition of human ENPP2 using FS3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0012	uM
[4-[[1-[(3,5-dichlorophenyl)methoxycarbonyl]piperidin-4-yl]carbamoyl]phenyl]methylphosphonic acid	1382928: Inhibition of human ENPP2 using FS3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0014	uM
8-[(1S)-1-[7-(4-methylcyclohexyl)oxy-8-(trifluoromethyl)naphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid	1768433: Inhibition of human ATX assessed as reduction in LPA formation using FS-3 as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by FRET assay	ic50	0.0014	uM
1-[4-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]-2-fluorophenyl]piperazin-1-yl]ethanone	1709586: Inhibition of recombinant human C-terminal His6-tagged ATX expressed in baculovirus infected Sf21 insect cells using LPC as substrate incubated for 2 hrs by rapidFire based MS/MS analysis	ic50	0.0015	uM
1-[4-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]phenyl]-2,2-dimethylpiperazin-1-yl]ethanone	1709586: Inhibition of recombinant human C-terminal His6-tagged ATX expressed in baculovirus infected Sf21 insect cells using LPC as substrate incubated for 2 hrs by rapidFire based MS/MS analysis	ic50	0.0016	uM
N-[(1R)-1-cyclohexyl-2-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-2-oxoethyl]-2-fluoro-3-methylbenzamide	1652836: Inhibition of C-terminal FLAG-tagged human autotaxin expressed in Freestyle 293 cells using synthetic substrate FS-3 by fluorescence based assay	ic50	0.0016	uM
[4-[[1-[[2-fluoro-4-(trifluoromethoxy)phenyl]methoxycarbonyl]piperidine-4-carbonyl]amino]phenyl]methylphosphonic acid	1382928: Inhibition of human ENPP2 using FS3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0017	uM
1-[2-ethyl-6-[4-[(4-hydroxypiperidin-1-yl)methyl]phenyl]-8-methylimidazo[1,2-a]pyridin-3-yl]-3-[(4-fluorophenyl)methyl]urea	1752374: Inhibition of human ATX using FS-3 as substrate preincubated for 45 mins followed by substrate addition and measured every 1 min for 30 mins by fluorescence microplate reader assay	ic50	0.0017	uM
1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-2-[2-(2H-triazol-4-yl)ethoxy]ethanone	1633000: Inhibition of recombinant full length human C-terminal His-tagged autotaxin expressed in human 293E cells assessed as choline release using lysophosphatidylcholine as substrate after 1 hr by Amplex red fluorescence assay	ic50	0.0017	uM
[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-[4-(2H-triazol-4-yl)-2-pyridinyl]methanone	1312315: Inhibition of recombinant human C-terminal His-tagged ATX expressed in HEK293E cells using lysophosphatidylcholine as substrate preincubated with enzyme followed by substrate addition measured after 1 hr by AmplexRed dye based fluorescence assay	ic50	0.0017	uM
[2-[[1-[(3,5-dichlorophenyl)methoxycarbonyl]piperidine-4-carbonyl]amino]-1,3-thiazol-4-yl]methylphosphonic acid	1382928: Inhibition of human ENPP2 using FS3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0018	uM
[4-[[1-[(3-chlorophenyl)methoxycarbonyl]piperidine-4-carbonyl]amino]phenyl]methylphosphonic acid	1382928: Inhibition of human ENPP2 using FS3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0018	uM
1-[5-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]phenyl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethanone	1709586: Inhibition of recombinant human C-terminal His6-tagged ATX expressed in baculovirus infected Sf21 insect cells using LPC as substrate incubated for 2 hrs by rapidFire based MS/MS analysis	ic50	0.0018	uM
6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]-N-[[4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]methyl]pyridazin-3-amine	1709586: Inhibition of recombinant human C-terminal His6-tagged ATX expressed in baculovirus infected Sf21 insect cells using LPC as substrate incubated for 2 hrs by rapidFire based MS/MS analysis	ic50	0.0018	uM
1-[4-[6-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]-3-pyridinyl]piperazin-1-yl]ethanone	1709586: Inhibition of recombinant human C-terminal His6-tagged ATX expressed in baculovirus infected Sf21 insect cells using LPC as substrate incubated for 2 hrs by rapidFire based MS/MS analysis	ic50	0.0019	uM
1-[4-[4-[[[6-[[6-(difluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]methyl]-3-(trifluoromethyl)phenyl]piperazin-1-yl]ethanone	1709586: Inhibition of recombinant human C-terminal His6-tagged ATX expressed in baculovirus infected Sf21 insect cells using LPC as substrate incubated for 2 hrs by rapidFire based MS/MS analysis	ic50	0.0019	uM
3-[6-chloro-2-cyclopropyl-1-(1-ethylpyrazol-4-yl)-7-fluoroindol-3-yl]sulfanyl-2-fluorobenzoic acid	1975197: Inhibition of ATX (unknown origin) using lysoPLD as substrate	ic50	0.0020	uM
N-[(1S)-1-(4-fluorophenyl)ethyl]-2-[3-[[4-(trifluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]sulfanylacetamide	1325587: Inhibition of human recombinant ATX using Rac-1-Palmitoyl-glycero-3-phosphocholine as substrate incubated for 2 hrs using ADHP fluorogenic peroxidase substrate by horseradish peroxidase/choline oxidase-coupled assay	ic50	0.0020	uM
N-[(1S)-1-(4-chlorophenyl)ethyl]-3-[3-[[4-(trifluoromethyl)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanamide	1325587: Inhibition of human recombinant ATX using Rac-1-Palmitoyl-glycero-3-phosphocholine as substrate incubated for 2 hrs using ADHP fluorogenic peroxidase substrate by horseradish peroxidase/choline oxidase-coupled assay	ic50	0.0020	uM
N-[(1S)-1-(4-chlorophenyl)ethyl]-3-[3-[[4-(difluoromethoxy)phenyl]methyl]imidazo[4,5-b]pyridin-2-yl]propanamide	1325587: Inhibition of human recombinant ATX using Rac-1-Palmitoyl-glycero-3-phosphocholine as substrate incubated for 2 hrs using ADHP fluorogenic peroxidase substrate by horseradish peroxidase/choline oxidase-coupled assay	ic50	0.0020	uM
sodium 3-[6-chloro-7-fluoro-2-methyl-1-(2-oxo-2-spiro[2H-indole-3,1’-cyclopropane]-1-ylethyl)indol-3-yl]sulfanyl-2-fluorobenzoate	1433833: Inhibition of ATX (unknown origin) using lysophosphatidyl choline as substrate	ic50	0.0020	uM
N-(2-ethyl-6-pyridin-3-ylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methyl-1,3-thiazol-2-amine	1458138: Inhibition of glycosylated human ATX using FS-3 as substrate preincubated for 30 mins followed by substrate addition measured after 30 mins by fluorescence assay	ic50	0.0020	uM
[4-[[1-[[4-(trifluoromethoxy)phenyl]methoxycarbonyl]piperidine-4-carbonyl]amino]phenyl]methylphosphonic acid	1382928: Inhibition of human ENPP2 using FS3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0020	uM
5-[[6-[[4-(4-acetylpiperazin-1-yl)phenyl]methylamino]pyridazin-3-yl]oxymethyl]pyridine-3-carbonitrile	1725673: Inhibition of recombinant human autotaxin assessed as reduction in LPA production using LPC as substrate after 2 hrs by Rapidfire-MS analysis	ic50	0.0020	uM
3-methyl-N-[(2R)-3-methyl-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl]benzamide	1652836: Inhibition of C-terminal FLAG-tagged human autotaxin expressed in Freestyle 293 cells using synthetic substrate FS-3 by fluorescence based assay	ic50	0.0020	uM
N-[(1R)-1-cyclohexyl-2-[3-[2-(methylamino)-2-oxoethyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl]-2-oxoethyl]-2-fluoro-3-methylbenzamide	1652836: Inhibition of C-terminal FLAG-tagged human autotaxin expressed in Freestyle 293 cells using synthetic substrate FS-3 by fluorescence based assay	ic50	0.0020	uM
sodium 3-[6-chloro-7-fluoro-2-methyl-1-(spiro[2H-indole-3,1’-cyclopropane]-1-carbonyl)indol-3-yl]sulfanyl-2-fluorobenzoate	1975200: Inhibition of human ATX using LPC as substrate assessed as choline release measured after 1.5 hrs by fluorescence based assay	ic50	0.0020	uM
(3,5-dichlorophenyl)methyl 4-[4-(2H-triazol-4-yl)butanoylamino]piperidine-1-carboxylate	1312292: Inhibition of human recombinant ATX expressed in HEK cells using oleoyl-lysophosphatidylcholine as substrate preincubated for 20 mins followed by substrate addition measured every 2 mins for 40 mins by AmplexRed dye based fluorescence assay	ic50	0.0020	uM
1-[[2-[3-[(Z)-N-(1,3-benzothiazol-2-ylamino)-C-(trifluoromethyl)carbonimidoyl]-1-ethylindol-5-yl]-1,3-thiazol-4-yl]methyl]piperidin-4-ol	1739783: Inhibition of human C-terminal His6-tagged ATX beta expressed in Sf9 insect cells using FS-3 as substrate preincubated for 45 mins followed by substrate addition and measured at 1 min interval for 30 mins by fluorescence assay	ic50	0.0021	uM
[3,5-bis(trifluoromethyl)phenyl]methyl (1S,5R)-6-[(2H-benzotriazole-5-carbonylamino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate	1349349: Inhibition of human ATX	ic50	0.0022	uM
[4-[2-[[1-[(3,5-dichlorophenyl)methoxycarbonyl]piperidin-4-yl]carbamoyl]-1,3-thiazol-4-yl]phenyl]methylphosphonic acid	1488985: Inhibition of human ATX using FS-3 as substrate measured every 5 mins for 30 mins by fluorescence assay	ic50	0.0022	uM
1-[5-[4-[[bis(2-hydroxyethyl)amino]methyl]-1,3-thiazol-2-yl]-1-ethylindol-3-yl]-3-[(3-chloro-4-methoxyphenyl)methyl]urea	1877071: Inhibition of human ATX using FS-3 as substrate preincubated for 45 mins followed by substrate addition measured every 1 min for 30 mins by fluorescence based microplate reader analysis	ic50	0.0022	uM
1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-(2H-triazol-4-yl)pentan-1-one	1633000: Inhibition of recombinant full length human C-terminal His-tagged autotaxin expressed in human 293E cells assessed as choline release using lysophosphatidylcholine as substrate after 1 hr by Amplex red fluorescence assay	ic50	0.0022	uM
1-[4-[4-[1-[[6-[[6-(trifluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]ethyl]phenyl]piperazin-1-yl]ethanone	1768410: Inhibition of recombinant human ATX using LPC as substrate incubated for 2 hrs by RapidFire autosampler system	ic50	0.0022	uM
3-fluoro-N-[(2R)-3-methyl-1-(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-1-oxobutan-2-yl]benzamide	1652836: Inhibition of C-terminal FLAG-tagged human autotaxin expressed in Freestyle 293 cells using synthetic substrate FS-3 by fluorescence based assay	ic50	0.0022	uM
N-[1-ethyl-3-[(4-fluorophenyl)methylcarbamoylamino]indol-5-yl]-4-[(4-hydroxypiperidin-1-yl)methyl]benzamide	1718120: Inhibition of glycosylated human ATX using FS-3 as substrate preincubated for 45 mins followed by substrate addition and measured every 1 min for 30 mins by fluorescence microplate reader assay	ic50	0.0023	uM
1-[4-[2-fluoro-4-[1-[[6-[[6-(trifluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]cyclopropyl]phenyl]piperazin-1-yl]ethanone	1768410: Inhibition of recombinant human ATX using LPC as substrate incubated for 2 hrs by RapidFire autosampler system	ic50	0.0024	uM
6-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]propanoyl]-3H-1,3-benzoxazol-2-one	1633000: Inhibition of recombinant full length human C-terminal His-tagged autotaxin expressed in human 293E cells assessed as choline release using lysophosphatidylcholine as substrate after 1 hr by Amplex red fluorescence assay	ic50	0.0025	uM
1-[4-[4-[1-[[6-[[6-(trifluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]cyclopropyl]phenyl]piperazin-1-yl]ethanone	1768410: Inhibition of recombinant human ATX using LPC as substrate incubated for 2 hrs by RapidFire autosampler system	ic50	0.0025	uM
1-[4-[4-[(1S)-1-[[6-[[6-(trifluoromethyl)-3-pyridinyl]methoxy]pyridazin-3-yl]amino]ethyl]phenyl]piperazin-1-yl]ethanone	1768410: Inhibition of recombinant human ATX using LPC as substrate incubated for 2 hrs by RapidFire autosampler system	ic50	0.0026	uM
3-(1,3-benzothiazol-2-yl)-1-[4-[(4-fluorophenyl)methyl]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]propan-1-one	1312313: Inhibition of human recombinant ATX using FS3 as substrate incubated for 30 mins by fluorescence assay	ic50	0.0026	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	5
Tetrachlorodibenzodioxin	increases expression, decreases reaction, increases activity, affects expression, decreases expression	5
Valproic Acid	affects cotreatment, increases expression	5
Cyclosporine	decreases expression	4
bisphenol A	decreases expression, increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
Aflatoxin B1	affects expression, affects methylation, decreases expression	3
KN 62	decreases reaction, increases expression, increases secretion	2
Panobinostat	increases expression, affects cotreatment	2
Cadmium	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
Toluene 2,4-Diisocyanate	increases expression, increases reaction, decreases reaction, increases secretion	2
Thapsigargin	decreases expression, increases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, increases expression	2
ONO-8430506	decreases activity, decreases abundance	1
bisphenol F	affects cotreatment, decreases expression	1
2-anisidine	decreases expression	1
coomassie Brilliant Blue	decreases reaction, increases secretion	1
methylmercuric chloride	decreases expression	1
captax	increases expression	1
cinnamyl anthranilate	increases expression, increases secretion, decreases reaction, affects cotreatment	1
1,2,3-trichloropropane	increases secretion	1
2-methyl-4-isothiazolin-3-one	increases expression	1
alpha-naphthoflavone	increases activity, decreases reaction	1
sulforaphane	decreases expression	1
2’,3’-dialdehyde ATP	decreases reaction, increases secretion	1
sodium arsenite	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
benzo(e)pyrene	decreases methylation	1
2,6-diisocyanatotoluene	increases expression, decreases reaction	1
potassium chromate(VI)	decreases expression	1

ChEMBL screening assays

305 unique, capped per target: 303 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1048405	Binding	Inhibition of human autotaxin isolated from MDA-MB-231 cells assessed as blockade of FS3 substrate hydrolysis by FRET assay	Optimization of a pipemidic acid autotaxin inhibitor. — J Med Chem
CHEMBL4619344	Functional	In vivo inhibition of lysoPLD activity of ATX in SCID mouse plasma xenografted with human MDA-MB-231 cells at 30 mg/kg, po administered twice daily for 32 days in combination with paclitaxel at 20 mg/kg, ip three times weekly for 5 weeks an	ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model. — ACS Med Chem Lett

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1661	ZR-75-30	Cancer cell line	Female
CVCL_B1RA	Abcam HeLa ENPP2 KO	Cancer cell line	Female
CVCL_D1SC	Abcam U-87MG ENPP2 KO	Cancer cell line	Male
CVCL_E1E8	Ubigene U-2932 ENPP2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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