ALPL

Summary

ALPL (alkaline phosphatase, biomineralization associated, HGNC:438) is a protein-coding gene on chromosome 1p36.12, encoding Alkaline phosphatase, tissue-nonspecific isozyme (P05186). Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis.

This gene encodes a member of the alkaline phosphatase family of proteins. There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The first three are located together on chromosome 2, while the tissue non-specific form is located on chromosome 1. The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature enzyme. This enzyme may play a role in bone mineralization. Mutations in this gene have been linked to hypophosphatasia, a disorder that is characterized by hypercalcemia and skeletal defects.

Source: NCBI Gene 249 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ALPL-related autosomal dominant hypophosphatasia (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 37
• Clinical variants (ClinVar): 1,610 total — 156 pathogenic, 217 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000478

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:438
Approved symbol	ALPL
Name	alkaline phosphatase, biomineralization associated
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	TNSALP, TNALP, TNAP
Ensembl gene	ENSG00000162551
Ensembl biotype	protein_coding
OMIM	171760
Entrez	249

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000374829, ENST00000374830, ENST00000374832, ENST00000374840, ENST00000468526, ENST00000539907, ENST00000540617, ENST00000879459

RefSeq mRNA: 6 — MANE Select: NM_000478 NM_000478, NM_001127501, NM_001177520, NM_001369803, NM_001369804, NM_001369805

CCDS: CCDS217, CCDS53274, CCDS53275

Canonical transcript exons

ENST00000374840 — 12 exons

Exon	Start	End
ENSE00001066195	21570305	21570374
ENSE00001066199	21573665	21573799
ENSE00001066201	21568104	21568247
ENSE00001066206	21564041	21564216
ENSE00001464806	21577383	21578410
ENSE00001464850	21553978	21554142
ENSE00001464852	21509423	21509517
ENSE00003569303	21563110	21563284
ENSE00003574693	21561097	21561212
ENSE00003585785	21560626	21560745
ENSE00003613168	21575733	21575924
ENSE00003735967	21576522	21576641

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 96.30.

FANTOM5 (CAGE): breadth broad, TPM avg 93.9172 / max 5673.2572, expressed in 864 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1164	90.4458	804
1168	0.9676	151
1189	0.4917	115
1166	0.3204	23
1163	0.2739	129
1171	0.2494	93
1197	0.2111	70
1170	0.2082	80
1186	0.1525	73
1185	0.1302	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	96.30	gold quality
right adrenal gland cortex	UBERON:0035827	95.61	gold quality
left adrenal gland cortex	UBERON:0035825	95.41	gold quality
right lobe of liver	UBERON:0001114	95.02	gold quality
left adrenal gland	UBERON:0001234	94.96	gold quality
adrenal cortex	UBERON:0001235	93.93	gold quality
upper lobe of lung	UBERON:0008948	93.16	gold quality
upper lobe of left lung	UBERON:0008952	93.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.07	gold quality
blood	UBERON:0000178	92.70	gold quality
adrenal gland	UBERON:0002369	92.33	gold quality
right lung	UBERON:0002167	91.04	gold quality
lower lobe of lung	UBERON:0008949	90.77	gold quality
spleen	UBERON:0002106	90.57	gold quality
apex of heart	UBERON:0002098	90.54	gold quality
adult mammalian kidney	UBERON:0000082	88.90	gold quality
tibia	UBERON:0000979	86.79	gold quality
liver	UBERON:0002107	86.70	gold quality
omental fat pad	UBERON:0010414	86.64	gold quality
peritoneum	UBERON:0002358	86.55	gold quality
nasal cavity epithelium	UBERON:0005384	85.71	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.06	gold quality
lung	UBERON:0002048	84.82	gold quality
cingulate cortex	UBERON:0003027	84.52	gold quality
anterior cingulate cortex	UBERON:0009835	84.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.29	gold quality
right atrium auricular region	UBERON:0006631	84.24	gold quality
heart left ventricle	UBERON:0002084	84.22	gold quality
cardiac ventricle	UBERON:0002082	83.45	gold quality
right frontal lobe	UBERON:0002810	83.29	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	817.28
E-HCAD-1	yes	90.43
E-CURD-114	yes	49.56
E-ANND-3	yes	25.75
E-GEOD-135922	yes	25.18
E-CURD-112	yes	13.14
E-MTAB-8271	yes	8.00
E-MTAB-10137	yes	5.57
E-MTAB-6678	no	2.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP4, BMP6, DLX5, FGF2, ID1, ID2, ID3, KLF4, LRP3, MSX2, PBX1, RUNX2, SMAD1, SMAD5, SP3, SP7, TNF, ZEB2

miRNA regulators (miRDB)

55 targeting ALPL, 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-9-5P	100.00	72.28	2361
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-520A-5P	99.35	66.72	1632

Literature-anchored findings (GeneRIF, showing 40)

• mutational analysis in patients with various forms of hypophosphatasia (PMID:11438998)
• candidate tumor suppressor gene in meningioma (PMID:11528114)
• regardless of clinical type, deletion in the TNSALP gene occurs frequently among Japanese patients with hypophosphatasia (PMID:11810413)
• the structural differences in human AP isoforms are demonstrated through models (PMID:12372831)
• apical uptake of organic cations in Caco-2 cells is affected by phosphorylation/dephosphorylation mechanisms, and ecto-ALP activity may be involved in this process (PMID:12397600)
• This study indicated that the mutation (G1144A) produced the inactive ALP enzyme and would be a disease-causing mutation of the childhood-type HOPS. (PMID:12412800)
• G317D mutation in the tissue-nonspecific alkaline phosphatase gene associated with childhood hypophosphatasia in a German family. (PMID:12638946)
• Inheritance, absence of malformations, increased serum alkaline phosphatase, peak bone mass decreasing physiologically with age, and involvement of cortical and trabecular bone suggest a new variant of hyperostosis/osteosclerosis. (PMID:12788869)
• Fifteen novel ALPL mutations have been found in a series of 11 families from various origins affected by perinatal and infantile hypophosphatasia. (PMID:12815606)
• Serum BAP should not be considered a good marker for the diagnosis of osteoporosis in men with prostate cancer. (PMID:14756545)
• Cyclic stretching and/or cocultivation with PBMCs decreased ALPase activity in periodontal ligament fibroblasts. The anabolic systemic hormone 1,25(OH)(2)D(3) increased ALPase activity. (PMID:15248185)
• analysis of residues determining the binding specificity of uncompetitive inhibitors to tissue-nonspecific alkaline phosphatase (PMID:15476587)
• Low serum level in osteochondrodysplasia. (PMID:15562030)
• mutant (A115V) TNSALP gene produced the defective ALP enzyme and it could be recessively transmitted and be a disease-causing mutation of the adult-type hypophosphatasia (PMID:15629439)
• variation in TNSALP may be an important determinant of age-related bone loss in humans (PMID:15824850)
• Our results suggest the involvement of androgen receptor positive chondrocytes in thyroid cartilage mineralization, probably by a testosterone-linked stimulation of alkaline phosphatase. (PMID:16583221)
• saliva AST and ALP may have roles in development of periodontal diseases (PMID:16681433)
• The role of the N-terminus and its microenvironment in determining the enzyme stability and catalysis using human placental (PLAP) and tissue-nonspecific AP (TNAP) as paradigms, is analyzed. (PMID:16893177)
• Our study demonstrates that the novel BALP B1x isoform is occasionally found to be present in children with kidney disease but to a lesser degree in comparison with adults with chronic kidney disease on dialysis. (PMID:16932897)
• TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with ankylosing spondylitis in multiplex families containing affected individuals of both sexes. (PMID:17195227)
• Pathologic fractures attributable to hypophosphatasia diagnosed in adulthood, and to missense mutation in TNSALP(C455G>A). (PMID:17229666)
• Serum bone-specific alkaline phosphatase total protein can be considered a sensitive marker of bone turnover and could be especially useful as valuable non-invasive biochemical marker for identifying sickle cell patients with bone complications. (PMID:17242729)
• Nine novel ALPL gene mutations in a series of 8 patients affected by various forms of hypophosphatasia. (PMID:17253930)
• Infantile hypophatasia caused by two novel missense mutations of TNSALP. (PMID:17395561)
• Cysteine inhibited TNAP’s phosphatase activity uncompetitively and its inorganic pyrophosphatase activity mix-competitively (PMID:17516619)
• Cuff tear arthropathy is associated with variants in ANKH and TNAP that alter extracellular inorganic pyrophosphate concentrations causing calcium crystal deposition. (PMID:17563703)
• While the wild-type protein reached the cell membrane within the first 24h after transfection, the mutants reached the membrane with delays of 24, 48 or 72 h. (PMID:17719863)
• The results provide an explanation of the lethal phenotype in the patient where the two ALPL alleles are non-functional and in the asymptomatic father where over-expression of the normal allele could counteract the effect of the c.1133A>T mutation. (PMID:17922851)
• Inverse relationships between neuropeptide Y (NPY) and biomarkers (bone and serum alkaline phosphatase) levels of bone turnover suggest that NPY may be implicated in low bone turnover in dialysis patients by a parathyroid-independent mechanism. (PMID:18037100)
• A monoclonal antibody against tissue-nonspecific alkaline phosphatase (ALP) is established that will be a useful tool for effective measurement of liver-ALP, a marker of liver disease, by immunocapture enzymatic assay. (PMID:18158785)
• Hypophosphatasia is an inheritable disease characterized by a deficiency of tissue non-specific alkaline phosphatase (TNAP or TNSALP) activity. The disease is due to mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL) encoding TNAP. (PMID:18328985)
• analysis of the structural importance of the crown domain with respect to the catalytic function of TNSALP (PMID:18422967)
• U(2)OS cells transfected with wild-type TNAP and polymorphism TNAP cDNA showed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) induction as in SaOS-2 cells. (PMID:18455459)
• These results suggest that phosphate derived from TNAP-induced hydrolysis of beta-glycerophosphate yields signals that induce TNAP expression. (PMID:18500657)
• Evaluation of a new compound heterozygous TNSALP mutation for its residual enzyme activity and localization in a case of infantile hypophsphatemia. (PMID:18523927)
• Elevated serum ALP is correlated with peripheral arterial disease, independent of other traditional cardiovascular risk factors (PMID:18572267)
• Results report for the first time that human B cell express bone specific alkaline phosphatase. (PMID:18579124)
• plasma alkaline phosphatase may have a role in systemic inflammation in Hong Kong Chinese, but it is unknown whether C-reactive protein has a similar role (PMID:18605934)
• patients with poor diabetes control have lower levels of IGF-1, and greater IGFBP-1, IGFBP-5, and bone-specific alkaline phosphatase (PMID:18665784)
• These results suggest that the significant difference in Km values between the proteins translated from alkaline phosphatase 787T > C and 787T may contribute to regulatory effects on bone metabolism. (PMID:18724009)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	alpl	ENSDARG00000015546
mus_musculus	Alpl	ENSMUSG00000028766
rattus_norvegicus	Alpl	ENSRNOG00000013954
drosophila_melanogaster	Alp4	FBGN0016123
drosophila_melanogaster	Alp11	FBGN0030661
drosophila_melanogaster	Alp12	FBGN0032779
drosophila_melanogaster	Alp6	FBGN0033423
drosophila_melanogaster	Alp7	FBGN0034710
drosophila_melanogaster	Alp8	FBGN0034712
drosophila_melanogaster	Alp10	FBGN0035619
drosophila_melanogaster	Alp9	FBGN0035620
drosophila_melanogaster	Alp13	FBGN0037786
drosophila_melanogaster	Alp5	FBGN0038845
drosophila_melanogaster	phu	FBGN0043791
drosophila_melanogaster	Alp1	FBGN0283479
drosophila_melanogaster	Alp2	FBGN0283480

Paralogs (3): ALPP (ENSG00000163283), ALPG (ENSG00000163286), ALPI (ENSG00000163295)

Protein

Protein identifiers

Alkaline phosphatase, tissue-nonspecific isozyme — P05186 (reviewed: P05186)

Alternative names: Alkaline phosphatase liver/bone/kidney isozyme, Phosphoamidase, Phosphocreatine phosphatase

All UniProt accessions (2): B1ANL0, P05186

UniProt curated annotations — full annotation on UniProt →

Function. Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis. Has broad substrate specificity and can hydrolyze a considerable variety of compounds: however, only a few substrates, such as diphosphate (inorganic pyrophosphate; PPi), pyridoxal 5’-phosphate (PLP) and N-phosphocreatine are natural substrates. Plays an essential role in skeletal and dental mineralization via its ability to hydrolyze extracellular diphosphate, a potent mineralization inhibitor, to phosphate: it thereby promotes hydroxyapatite crystal formation and increases inorganic phosphate concentration. Acts in a non-redundant manner with PHOSPHO1 in skeletal mineralization: while PHOSPHO1 mediates the initiation of hydroxyapatite crystallization in the matrix vesicles (MVs), ALPL/TNAP catalyzes the spread of hydroxyapatite crystallization in the extracellular matrix. Also promotes dephosphorylation of osteopontin (SSP1), an inhibitor of hydroxyapatite crystallization in its phosphorylated state; it is however unclear whether ALPL/TNAP mediates SSP1 dephosphorylation via a direct or indirect manner. Catalyzes dephosphorylation of PLP to pyridoxal (PL), the transportable form of vitamin B6, in order to provide a sufficient amount of PLP in the brain, an essential cofactor for enzymes catalyzing the synthesis of diverse neurotransmitters. Additionally, also able to mediate ATP degradation in a stepwise manner to adenosine, thereby regulating the availability of ligands for purinergic receptors. Also capable of dephosphorylating microbial products, such as lipopolysaccharides (LPS) as well as other phosphorylated small-molecules, such as poly-inosine:cytosine (poly I:C). Acts as a key regulator of adaptive thermogenesis as part of the futile creatine cycle: localizes to the mitochondria of thermogenic fat cells and acts by mediating hydrolysis of N-phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. During the futile creatine cycle, creatine and N-phosphocreatine are in a futile cycle, which dissipates the high energy charge of N-phosphocreatine as heat without performing any mechanical or chemical work.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane. Extracellular vesicle membrane. Mitochondrion membrane. Mitochondrion intermembrane space.

Post-translational modifications. N-glycosylated.

Disease relevance. Hypophosphatasia (HOPS) [MIM:146300] A metabolic bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Four forms are distinguished, depending on the age of onset: perinatal, infantile, childhood and adult type. The perinatal form is the most severe and is almost always fatal. The adult form is mild and characterized by recurrent fractures, osteomalacia, rickets, and loss of teeth. Some cases are asymptomatic, while some patients manifest dental features without skeletal manifestations (odontohypophosphatasia). The disease is caused by variants affecting the gene represented in this entry. Hypophosphatasia, childhood (HPPC) [MIM:241510] A bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. The disease is caused by variants affecting the gene represented in this entry. Hypophosphatasia, infantile (HPPI) [MIM:241500] A severe bone disease characterized by defective skeletal mineralization and biochemically by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase. Three more or less distinct types of infantile hypophosphatasia can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe ‘rachitic’ skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Phosphatase activity is specifically inhibited by 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425).

Cofactor. Binds 1 Mg(2+) ion. Binds 2 Zn(2+) ions.

Domain organisation. Calcium-binding is structural and does not influence the alkaline phosphatase activity. At very high concentrations, calcium can however substitute for zinc at zinc-binding sites, leading to strongly reduced enzyme activity.

Miscellaneous. In most mammals there are four different isozymes: placental (ALPP), germ cell (ALPG), intestinal (ALPI) and tissue non-specific (liver/bone/kidney) (ALPL/TNAP).

Similarity. Belongs to the alkaline phosphatase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P05186-1	1	yes
P05186-2	2
P05186-3	3

RefSeq proteins (6): NP_000469, NP_001120973, NP_001170991, NP_001356732, NP_001356733, NP_001356734 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001952	Alkaline_phosphatase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR018299	Alkaline_phosphatase_AS	Active_site

Pfam: PF00245

Enzyme classification (BRENDA):

• EC 3.1.3.1 — alkaline phosphatase (BRENDA: 134 organisms, 346 substrates, 667 inhibitors, 331 Km, 180 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
4-NITROPHENYL PHOSPHATE	—	218
P-NITROPHENYL PHOSPHATE	0.0094–5.02	37
PHENYL PHOSPHATE	6.1–101.2	13
3-(4-METHOXYSPIRO [1,2-DIOXETANE-3,2’-(5’-CHLORO	0.037–0.1159	7
BETA-GLYCEROPHOSPHATE	0.3–3.35	7
ATP	0.1–5.7	5
DIPHOSPHATE	0.12–4	5
2-CHLORO-5-(4-METHOXYSPIRO (1,2-DIOXETANE-3,2’-(	0.01–0.177	3
2-NAPHTHYL PHOSPHATE	0.026–0.078	2
ADP	2.26–4.4	2
GLUCOSE 1-PHOSPHATE	2.22–4.8	2
PHOSPHO-DL-THR	0.39–0.9	2
PHOSPHO-DL-TYR	0.4–0.72	2
PHOSPHO-L-SER	0.38–0.68	2
PYRIDOXAL PHOSPHATE	0.2–0.37	2

Catalyzed reactions (Rhea), 8 shown:

• N-phosphocreatine + H2O = creatine + phosphate (RHEA:12977)
• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• a phosphate monoester + H2O = an alcohol + phosphate (RHEA:15017)
• phosphoethanolamine + H2O = ethanolamine + phosphate (RHEA:16089)
• pyridoxal 5’-phosphate + H2O = pyridoxal + phosphate (RHEA:20533)
• diphosphate + H2O = 2 phosphate + H(+) (RHEA:24576)
• AMP + H2O = adenosine + phosphate (RHEA:29375)
• ADP + H2O = AMP + phosphate + H(+) (RHEA:61436)

UniProt features (200 total): sequence variant 117, helix 21, strand 18, binding site 14, mutagenesis site 6, turn 5, glycosylation site 5, sequence conflict 4, disulfide bond 2, splice variant 2, signal peptide 1, chain 1, modified residue 1, lipid moiety-binding region 1, propeptide 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9SH5	ELECTRON MICROSCOPY	2.27
7YIW	X-RAY DIFFRACTION	2.89
7YIX	ELECTRON MICROSCOPY	2.96
7YIV	X-RAY DIFFRACTION	3.18
9S0V	X-RAY DIFFRACTION	3.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05186-F1	93.74	0.91

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

Functional residue map

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

Catalytic / active sites (1): 110 (phosphoserine intermediate)

Ligand- & substrate-binding residues (14): 291; 306; 332; 337; 341; 378; 379; 454; 60; 60; 110; 173 …

Post-translational modifications (2): 110, 501

Disulfide bonds (2): 139–201, 489–497

Glycosylation sites (5): 140, 230, 271, 303, 430

Mutagenesis-validated functional residues (6):

Position	Phenotype
235	abolished alkaline phosphatase activity.
270	reduced alkaline phosphatase activity.
272	reduced alkaline phosphatase activity.
290	abolished alkaline phosphatase activity.
291	reduced alkaline phosphatase activity.
306	abolished alkaline phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins

MSigDB gene sets: 357 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, MODULE_545, GOBP_RESPONSE_TO_CORTICOSTEROID, MODULE_45, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_TOOTH_MINERALIZATION, GOBP_REPLACEMENT_OSSIFICATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_DEVELOPMENT, GOBP_RESPONSE_TO_INSULIN

GO Biological Process (22): skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), endochondral ossification (GO:0001958), developmental process involved in reproduction (GO:0003006), cellular homeostasis (GO:0019725), bone mineralization (GO:0030282), response to lipopolysaccharide (GO:0032496), response to insulin (GO:0032868), response to vitamin D (GO:0033280), response to vitamin B6 (GO:0034516), response to macrophage colony-stimulating factor (GO:0036005), pyridoxal 5’-phosphate metabolic process (GO:0042822), response to antibiotic (GO:0046677), response to glucocorticoid (GO:0051384), phosphate ion homeostasis (GO:0055062), calcium ion homeostasis (GO:0055074), cementum mineralization (GO:0071529), positive regulation of cold-induced thermogenesis (GO:0120162), futile creatine cycle (GO:0140651), inhibition of non-skeletal tissue mineralization (GO:0140928), response to sodium phosphate (GO:1904383), biomineral tissue development (GO:0031214)

GO Molecular Function (12): alkaline phosphatase activity (GO:0004035), inorganic diphosphate phosphatase activity (GO:0004427), calcium ion binding (GO:0005509), pyrophosphatase activity (GO:0016462), ATP hydrolysis activity (GO:0016887), pyridoxal phosphatase activity (GO:0033883), ADP phosphatase activity (GO:0043262), phosphoamidase activity (GO:0050187), phosphoethanolamine phosphatase activity (GO:0052732), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), metal ion binding (GO:0046872)

GO Cellular Component (11): extracellular region (GO:0005576), mitochondrial intermembrane space (GO:0005758), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular matrix (GO:0031012), mitochondrial membrane (GO:0031966), extracellular exosome (GO:0070062), side of membrane (GO:0098552), obsolete extracellular space (GO:0005615), mitochondrion (GO:0005739), extracellular membrane-bounded organelle (GO:0065010)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to oxygen-containing compound	3
phosphatase activity	3
cellular anatomical structure	3
ossification	2
response to lipid	2
response to vitamin	2
inorganic ion homeostasis	2
mitochondrial envelope	2
membrane	2
system development	1
cell differentiation	1
replacement ossification	1
endochondral bone morphogenesis	1
reproductive process	1
developmental process	1
homeostatic process	1
biomineral tissue development	1
response to molecule of bacterial origin	1
response to peptide hormone	1
response to nitrogen compound	1
response to cytokine	1
aldehyde metabolic process	1
organophosphate metabolic process	1
vitamin B6 metabolic process	1
response to chemical	1
response to corticosteroid	1
monoatomic cation homeostasis	1
tooth mineralization	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
creatine kinase activity	1
metabolic process	1
phosphoamidase activity	1
adaptive thermogenesis	1
tissue homeostasis	1
pyrophosphatase activity	1
metal ion binding	1
hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides	1
ribonucleoside triphosphate phosphatase activity	1

Protein interactions and networks

STRING

2100 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALPL	BGLAP	P02818	901
ALPL	RUNX2	Q13950	891
ALPL	SLC30A7	Q8NEW0	887
ALPL	NBPF3	Q9H094	886
ALPL	SLC30A6	Q6NXT4	885
ALPL	ENPP1	P22413	864
ALPL	SLC30A5	Q8TAD4	857
ALPL	PHOSPHO1	Q8TCT1	832
ALPL	IBSP	P21815	827
ALPL	COL1A1	P02452	826
ALPL	SP7	Q8TDD2	781
ALPL	REEP3	Q6NUK4	763
ALPL	BMP2	P12643	757
ALPL	SPP1	P10451	715
ALPL	ANKH	Q9HCJ1	713

IntAct

12 interactions, top by confidence:

A	B	Type	Score
ALPL	SPCS2	psi-mi:“MI:0914”(association)	0.530
NLRP12	ALPL	psi-mi:“MI:0915”(physical association)	0.370
L1TD1	MYO1C	psi-mi:“MI:0914”(association)	0.350
VMP1	TPM3	psi-mi:“MI:0914”(association)	0.350
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
ALPL	EIF4A2	psi-mi:“MI:0915”(physical association)	0.000
alsB	ALPL	psi-mi:“MI:0915”(physical association)	0.000
LCOR	ALPL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (34): ALPL (Biochemical Activity), ALOX5 (Biochemical Activity), SPCS2 (Affinity Capture-MS), SEC11C (Affinity Capture-MS), MAPKAPK2 (Negative Genetic), PIK3C2B (Negative Genetic), RPS6KA2 (Negative Genetic), CDC25A (Negative Genetic), NDUFB1 (Positive Genetic), MAP4K1 (Positive Genetic), EDA (Positive Genetic), ALPL (Affinity Capture-MS), ALPL (Affinity Capture-MS), ALPL (Affinity Capture-MS), ALPL (Affinity Capture-MS)

ESM2 similar proteins: A0A2I4HXH5, B6EWW8, F8S0Z7, O35409, O77564, P04062, P04068, P05106, P05186, P05187, P07099, P08289, P09242, P09487, P09923, P10696, P15693, P17439, P19111, P21588, P21589, P24822, P24823, P28492, P51740, P58242, P70627, P83456, Q04609, Q05927, Q13822, Q17QK3, Q29486, Q2KHZ8, Q3TIW9, Q571F8, Q5EZ72, Q5R8E3, Q5RDN7, Q61503

Diamond homologs: O60109, P00634, P05186, P08289, P09242, P09487, P11491, P19147, P19405, P19406, P21948, Q29486, P09401, P35483, P83456, Q02QC9, Q92058, P05187, P09923, P10696, P15693, P19111, P24822, P24823, P29523, P51740, Q24238

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
RUNX2	“up-regulates quantity by expression”	ALPL	“transcriptional regulation”
BMP2	up-regulates	ALPL
GDF2	up-regulates	ALPL
WNT3A	up-regulates	ALPL
FGF2	“down-regulates quantity by repression”	ALPL	“transcriptional regulation”
ALPL	up-regulates	Bone_mineralization
ALPL	“down-regulates activity”	MAPT	dephosphorylation
ALPL	“down-regulates activity”	SPP1	dephosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1610 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	156
Likely pathogenic	217
Uncertain significance	362
Likely benign	459
Benign	74

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064140	NM_000478.6(ALPL):c.335G>C (p.Gly112Ala)	Pathogenic
1066773	NC_000001.10:g.(?21900138)(21900312_?)del	Pathogenic
1070177	NM_000478.6(ALPL):c.212G>A (p.Arg71His)	Pathogenic
1071140	NM_000478.6(ALPL):c.886C>T (p.Gln296Ter)	Pathogenic
1073912	NM_000478.6(ALPL):c.558G>A (p.Trp186Ter)	Pathogenic
1074110	NC_000001.10:g.(?21880565)(21904151_?)del	Pathogenic
1075198	NM_000478.6(ALPL):c.412del (p.Arg138fs)	Pathogenic
1353756	NM_000478.6(ALPL):c.534C>A (p.Tyr178Ter)	Pathogenic
1355608	NM_000478.6(ALPL):c.480del (p.Val161fs)	Pathogenic
13662	NM_000478.6(ALPL):c.535G>A (p.Ala179Thr)	Pathogenic
13663	NM_000478.6(ALPL):c.211C>T (p.Arg71Cys)	Pathogenic
13664	NM_000478.6(ALPL):c.881A>C (p.Asp294Ala)	Pathogenic
13671	NM_000478.6(ALPL):c.1133A>T (p.Asp378Val)	Pathogenic
13674	NM_000478.6(ALPL):c.1559del (p.Leu520fs)	Pathogenic
13677	NM_000478.6(ALPL):c.346G>A (p.Ala116Thr)	Pathogenic
13678	NM_000478.6(ALPL):c.648+1G>A	Pathogenic
13680	NM_000478.6(ALPL):c.323C>T (p.Pro108Leu)	Pathogenic
13682	NM_000478.6(ALPL):c.746G>T (p.Gly249Val)	Pathogenic
13684	NM_000478.6(ALPL):c.814C>T (p.Arg272Cys)	Pathogenic
1394226	NC_000001.10:g.(?21887109)(21887715_?)del	Pathogenic
1425963	NM_000478.6(ALPL):c.1164C>A (p.Tyr388Ter)	Pathogenic
1435973	NM_000478.6(ALPL):c.896T>C (p.Leu299Pro)	Pathogenic
1439050	NM_000478.6(ALPL):c.551G>A (p.Arg184Gln)	Pathogenic
1451581	NC_000001.10:g.(?21887099)(21904141_?)del	Pathogenic
1457398	NM_000478.6(ALPL):c.1367G>C (p.Gly456Ala)	Pathogenic
1457576	NM_000478.6(ALPL):c.1231A>G (p.Thr411Ala)	Pathogenic
1457899	NM_000478.6(ALPL):c.1286_1299dup (p.Val434fs)	Pathogenic
1458303	NM_000478.6(ALPL):c.1023T>A (p.His341Gln)	Pathogenic
189001	NM_000478.6(ALPL):c.667C>T (p.Arg223Trp)	Pathogenic
189023	NM_000478.6(ALPL):c.809G>A (p.Trp270Ter)	Pathogenic

SpliceAI

2036 predictions. Top by Δscore:

Variant	Effect	Δscore
1:21509515:CAGG:C	donor_loss	1.0000
1:21509518:GTAA:G	donor_loss	1.0000
1:21560622:TTA:T	acceptor_loss	1.0000
1:21560623:TA:T	acceptor_loss	1.0000
1:21560624:A:AC	acceptor_loss	1.0000
1:21560624:A:AG	acceptor_gain	1.0000
1:21560625:G:GG	acceptor_gain	1.0000
1:21560625:GA:G	acceptor_gain	1.0000
1:21560625:GAGA:G	acceptor_gain	1.0000
1:21560625:GAGAA:G	acceptor_gain	1.0000
1:21560715:GC:G	donor_gain	1.0000
1:21560742:GATG:G	donor_gain	1.0000
1:21560746:GTG:G	donor_loss	1.0000
1:21563106:GCAGA:G	acceptor_loss	1.0000
1:21563107:CAG:C	acceptor_loss	1.0000
1:21563108:A:AG	acceptor_gain	1.0000
1:21563108:AGAC:A	acceptor_gain	1.0000
1:21563109:G:GT	acceptor_gain	1.0000
1:21563109:GA:G	acceptor_gain	1.0000
1:21563109:GAC:G	acceptor_gain	1.0000
1:21563109:GACG:G	acceptor_gain	1.0000
1:21563109:GACGT:G	acceptor_gain	1.0000
1:21563281:GCTG:G	donor_gain	1.0000
1:21563282:CTGGT:C	donor_loss	1.0000
1:21563283:TG:T	donor_gain	1.0000
1:21563283:TGGT:T	donor_loss	1.0000
1:21563284:GG:G	donor_gain	1.0000
1:21563285:G:GG	donor_gain	1.0000
1:21563285:GTG:G	donor_loss	1.0000
1:21563286:T:G	donor_loss	1.0000

AlphaMissense

3443 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:21563140:A:C	S110R	0.999
1:21563142:T:A	S110R	0.999
1:21563142:T:G	S110R	0.999
1:21563178:G:C	K122N	0.999
1:21563178:G:T	K122N	0.999
1:21568192:G:T	R246M	0.999
1:21575745:A:C	D337A	0.999
1:21575745:A:T	D337V	0.999
1:21575746:C:A	D337E	0.999
1:21575746:C:G	D337E	0.999
1:21560716:C:A	A51D	0.998
1:21560743:A:T	D60V	0.998
1:21560745:G:T	G61W	0.998
1:21561121:C:A	A69D	0.998
1:21561127:G:C	R71P	0.998
1:21563152:G:C	A114P	0.998
1:21563159:C:A	A116D	0.998
1:21563197:G:T	G129W	0.998
1:21564091:A:C	S175R	0.998
1:21564093:C:A	S175R	0.998
1:21564093:C:G	S175R	0.998
1:21564175:G:C	D203H	0.998
1:21568192:G:C	R246T	0.998
1:21568193:G:C	R246S	0.998
1:21568193:G:T	R246S	0.998
1:21575756:C:G	H341D	0.998
1:21575807:G:C	A358P	0.998
1:21575868:A:T	D378V	0.998
1:21576584:G:T	G418W	0.998
1:21576585:G:A	G418E	0.998

dbSNP variants (sampled 300 via entrez): RS1000112840 (1:21560059 A>C), RS1000124283 (1:21517551 A>G), RS1000128583 (1:21541939 C>T), RS1000136670 (1:21511541 T>G), RS1000146953 (1:21573413 G>C), RS1000153954 (1:21517819 C>T), RS1000165234 (1:21559881 C>G,T), RS1000172841 (1:21518699 T>A), RS1000281312 (1:21547560 C>T), RS1000328561 (1:21577017 C>A,T), RS1000468983 (1:21571384 A>C), RS1000473736 (1:21530063 C>T), RS1000489130 (1:21542131 C>T), RS1000533834 (1:21576303 A>G), RS1000555177 (1:21528963 A>G)

Disease associations

OMIM: gene MIM:171760 | disease phenotypes: MIM:146300, MIM:241510, MIM:241500, MIM:166200, MIM:132400, MIM:301040

GenCC curated gene-disease

Disease	Classification	Inheritance
childhood hypophosphatasia	Definitive	Autosomal recessive
hypophosphatasia	Definitive	Autosomal recessive
adult hypophosphatasia	Strong	Autosomal dominant
infantile hypophosphatasia	Strong	Autosomal recessive
perinatal lethal hypophosphatasia	Supportive	Autosomal recessive
odontohypophosphatasia	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
ALPL-related autosomal dominant hypophosphatasia	Definitive	AD
ALPL-related autosomal recessive hypophosphatasia	Definitive	AR

Mondo (17): hypophosphatasia (MONDO:0018570), adult hypophosphatasia (MONDO:1010154), childhood hypophosphatasia (MONDO:1010168), infantile hypophosphatasia (MONDO:1010169), osteogenesis imperfecta (MONDO:0019019), multiple epiphyseal dysplasia (MONDO:0016648), odontohypophosphatasia (MONDO:0016607), ALPL-related autosomal dominant hypophosphatasia (MONDO:0100608), ALPL-related autosomal recessive hypophosphatasia (MONDO:0100609), perinatal lethal hypophosphatasia (MONDO:0016605), connective tissue disorder (MONDO:0003900), hypophosphatemia (MONDO:0000313), alpha thalassemia-X-linked intellectual disability syndrome (MONDO:0010519), microcephaly (MONDO:0001149), (MONDO:0007798)

Orphanet (9): Infantile hypophosphatasia (Orphanet:247651), Childhood-onset hypophosphatasia (Orphanet:247667), Adult hypophosphatasia (Orphanet:247676), Hypophosphatasia (Orphanet:436), Osteogenesis imperfecta (Orphanet:666), Multiple epiphyseal dysplasia (Orphanet:251), Odontohypophosphatasia (Orphanet:247685), Perinatal lethal hypophosphatasia (Orphanet:247623), X-linked alpha-thalassemia-intellectual disability syndrome (Orphanet:847)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000164	Abnormality of the dentition
HP:0000268	Dolichocephaly
HP:0000520	Proptosis
HP:0000592	Blue sclerae
HP:0000670	Carious teeth
HP:0000737	Irritability
HP:0000773	Short ribs
HP:0000897	Rachitic rosary
HP:0000926	Platyspondyly
HP:0000934	Chondrocalcinosis
HP:0001024	Skin dimple over apex of long bone angulation
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001363	Craniosynostosis
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001561	Polyhydramnios
HP:0001760	Abnormal foot morphology
HP:0001903	Anemia
HP:0001945	Fever
HP:0002007	Frontal bossing
HP:0002013	Vomiting
HP:0002019	Constipation
HP:0002039	Anorexia
HP:0002104	Apnea
HP:0002150	Hypercalciuria
HP:0002170	Intracranial hemorrhage

GWAS associations

37 associations (top):

Study	Trait	p-value
GCST000248_1	Liver enzyme levels	7.000000e-15
GCST000358_1	Folate pathway vitamin levels	8.000000e-18
GCST000483_8	Folate pathway vitamin levels	1.000000e-15
GCST000583_13	Hematological and biochemical traits	5.000000e-13
GCST000703_1	Phosphorus levels	1.000000e-27
GCST001217_30	Metabolic traits	3.000000e-20
GCST001276_11	Liver enzyme levels (alkaline phosphatase)	2.000000e-50
GCST001510_3	Response to TNF-alpha inhibitors in rheumatoid arthritis	6.000000e-06
GCST001998_6	Adverse response to chemotherapy (neutropenia/leucopenia) (all platinum-based drugs)	9.000000e-06
GCST002559_2	Vitamin B levels in ischemic stroke	7.000000e-10
GCST003086_1	Kidney stones	6.000000e-10
GCST005981_7	Phosphorus levels	7.000000e-18
GCST006016_30	Serum alkaline phosphatase levels	4.000000e-130
GCST006799_1	Pyridoxal 5’-phosphate levels	2.000000e-16
GCST006979_858	Heel bone mineral density	2.000000e-11
GCST007260_1	B6 vitamer levels (multivariate analysis)	8.000000e-10
GCST007833_1	Urolithiasis	3.000000e-10
GCST009391_968	Metabolite levels	4.000000e-06
GCST009470_1	Plasma pyridoxal phosphate to pyridoxal ratio	1.000000e-08
GCST009471_1	Pyridoxal 5’-phosphate levels	7.000000e-16
GCST009598_1	Kidney stones	3.000000e-11
GCST009599_4	Kidney stones	4.000000e-09
GCST009599_5	Kidney stones	6.000000e-11
GCST009652_34	Serum alkaline phosphatase levels	4.000000e-110
GCST009652_35	Serum alkaline phosphatase levels	3.000000e-51
GCST009652_36	Serum alkaline phosphatase levels	7.000000e-27
GCST009652_37	Serum alkaline phosphatase levels	4.000000e-12
GCST009652_39	Serum alkaline phosphatase levels	6.000000e-52
GCST009652_40	Serum alkaline phosphatase levels	1.000000e-35
GCST009652_41	Serum alkaline phosphatase levels	2.000000e-20

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement
EFO:0004621	vitamin B6 measurement
EFO:0004861	phosphorus measurement
EFO:0004725	metabolite measurement
EFO:0004653	response to TNF antagonist
EFO:0009270	heel bone mineral density
EFO:0005116	urinary metabolite measurement
EFO:0000266	aortic stenosis

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D007014	Hypophosphatasia	C16.320.565.618.482; C18.452.648.618.482
D017674	Hypophosphatemia	C18.452.750.400
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
C538258	ATR-X syndrome (supp.)
C562440	Hypophosphatasia, Childhood (supp.)
C564146	Odontohypophosphatasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5979 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 144,380 (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
CHEMBL1200348	SULCONAZOLE NITRATE	4	3,129
CHEMBL1355736	THEOPHYLLINE	4	752
CHEMBL1454	LEVAMISOLE	4	56,423
CHEMBL1559	MICONAZOLE NITRATE	4	8,960
CHEMBL1770	LEVAMISOLE HYDROCHLORIDE	4	53,323
CHEMBL250450	ISOQUERCETIN	2	1,626
CHEMBL583912	(-)-EPICATECHIN	2	20,167

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs885814	ALPL		0.00	0

Binding affinities (BindingDB)

687 measured of 1226 human assays (1270 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-ethoxy-5-fluoro-N-(5-oxospiro[2,4-dihydropyrido[3,2-f][1,4]oxazepine-3,1’-cyclopropane]-7-yl)benzenesulfonamide	IC50	0.6 nM	US-9879032: Pyridine compounds
5-(hydroxymethyl)-2-methoxy-N-(5-oxospiro[2,4-dihydropyrido[3,2-f][1,4]oxazepine-3,1’-cyclopropane]-7-yl)benzenesulfonamide	IC50	1 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-(5-oxospiro[2,4-dihydropyrido[3,2-f][1,4]oxazepine-3,1’-cyclopropane]-7-yl)benzenesulfonamide	IC50	1.1 nM	US-9879032: Pyridine compounds
5-bromo-N-[(3S)-3-(hydroxymethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	1.2 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-(5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	1.4 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-(5-oxo-3-pyridin-3-yl-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	1.4 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	1.5 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3S)-3-(hydroxymethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide	IC50	1.6 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-[(3S)-3-methyl-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide	IC50	1.7 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3S)-3-ethyl-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	1.7 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3S)-3-(2-hydroxyethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	1.9 nM	US-9879032: Pyridine compounds
5-chloro-N-(5-oxospiro[2,4-dihydropyrido[3,2-f][1,4]oxazepine-3,1’-cyclopropane]-7-yl)-2-(trifluoromethoxy)benzenesulfonamide	IC50	1.9 nM	US-9879032: Pyridine compounds
5-fluoro-2-methoxy-N-(5-oxospiro[2,4-dihydropyrido[3,2-f][1,4]oxazepine-3,1’-cyclopropane]-7-yl)benzenesulfonamide	IC50	2.2 nM	US-9879032: Pyridine compounds
5-fluoro-N-(5-oxospiro[2,4-dihydropyrido[3,2-f][1,4]oxazepine-3,1’-cyclopropane]-7-yl)-2-(trifluoromethoxy)benzenesulfonamide	IC50	2.7 nM	US-9879032: Pyridine compounds
5-Chloro-N-(5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-(trifluoromethoxy)benzenesulfonamide	IC50	3.4 nM	US-10221195: Pyridine compounds
5-fluoro-2-methoxy-N-[(3S)-3-methyl-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide	IC50	3.5 nM	US-9879032: Pyridine compounds
5-fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	3.6 nM	US-9879032: Pyridine compounds
5-(hydroxymethyl)-N-[(3S)-3-(hydroxymethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	3.8 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3S)-3,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	3.9 nM	US-9879032: Pyridine compounds
5-fluoro-2-methoxy-N-(5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	4 nM	US-9879032: Pyridine compounds
5-fluoro-N-[(3S)-3-(hydroxymethyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]-2-(trifluoromethoxy)benzenesulfonamide	IC50	4.1 nM	US-9879032: Pyridine compounds
N-(2-hydroxyethyl)-3-(2,3,4-trichlorophenyl)-1H-pyrazole-5-carboxamide	IC50	4.22 nM
5-(hydroxymethyl)-2-methoxy-N-(5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	4.8 nM	US-9879032: Pyridine compounds
5-chloro-N-[4-(2-hydroxyethyl)-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	6.1 nM	US-9879032: Pyridine compounds
5-chloro-N-(3,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide	IC50	6.2 nM	US-9879032: Pyridine compounds
5-Chloro-2-methoxy-N-(4-methyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	6.3 nM	US-9879032: Pyridine compounds
N-[(3S)-3,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide	IC50	6.4 nM	US-9879032: Pyridine compounds
2-[(3S)-7-[(5-chloro-2-methoxyphenyl)sulfonylamino]-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-3-yl]-N,N-dimethylacetamide	IC50	6.7 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3S)-3-ethyl-4-methyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	7.2 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-[(3S)-5-oxo-3-propan-2-yl-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide	IC50	8.7 nM	US-9879032: Pyridine compounds
5-chloro-N-[4-[[2-(hydroxymethyl)-4-methoxyphenyl]methyl]-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	9.1 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-[4-(2-methoxyethyl)-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide	IC50	10.7 nM	US-9879032: Pyridine compounds
N-(3,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)-5-fluoro-2-methoxybenzenesulfonamide	IC50	12.6 nM	US-9879032: Pyridine compounds
5-fluoro-2-methoxy-N-(4-methyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	12.7 nM	US-9879032: Pyridine compounds
5-chloro-N-(4-ethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide	IC50	12.8 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-(5-oxo-4-pyridin-3-yl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	13.2 nM	US-9879032: Pyridine compounds
2-methoxy-N-(5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	13.4 nM	US-9879032: Pyridine compounds
7-[(5-chloro-2-methoxyphenyl)sulfonylamino]-N,N-dimethyl-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepine-3-carboxamide	IC50	14.6 nM	US-9879032: Pyridine compounds
N-(4-ethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)-5-fluoro-2-methoxybenzenesulfonamide	IC50	22.9 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-(5-oxo-4-pyridin-2-yl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	24.4 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-[3-(morpholine-4-carbonyl)-5-oxo-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-7-yl]benzenesulfonamide	IC50	25.2 nM	US-9879032: Pyridine compounds
5-chloro-N-[(3R)-3,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-2-methoxybenzenesulfonamide	IC50	27.1 nM	US-9879032: Pyridine compounds
3-(2,4-dichlorophenyl)-N-(3-hydroxypropyl)-1H-pyrazole-5-carboxamide	IC50	31.3 nM
3-(2,4-dichlorophenyl)-N-(4-hydroxybutyl)-1H-pyrazole-5-carboxamide	IC50	34.5 nM
3-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	IC50	35 nM
5-chloro-N-(2,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)-2-methoxybenzenesulfonamide	IC50	36.2 nM	US-9879032: Pyridine compounds
5-chloro-2-methoxy-N-(5-oxo-4-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl)benzenesulfonamide	IC50	43.4 nM	US-9879032: Pyridine compounds
N-[(3R)-3,4-dimethyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-7-yl]-5-fluoro-2-methoxybenzenesulfonamide	IC50	46 nM	US-9879032: Pyridine compounds
3-(2,4-dichlorophenyl)-N-(2-methoxyethyl)-1H-pyrazole-5-carboxamide	IC50	46.4 nM
3-(2,4-dichlorophenyl)-N,N-bis(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	IC50	46.8 nM

ChEMBL bioactivities

647 potent at pChembl≥5 of 1138 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.40	IC50	0.4	nM	CHEMBL6001738
9.40	IC50	0.4	nM	CHEMBL5748322
9.30	IC50	0.5	nM	CHEMBL5777450
9.30	IC50	0.5	nM	CHEMBL5836952
9.22	IC50	0.6	nM	CHEMBL6028619
9.22	IC50	0.6	nM	CHEMBL5870362
9.22	IC50	0.6	nM	CHEMBL5862935
9.10	IC50	0.8	nM	CHEMBL5935757
9.05	IC50	0.9	nM	CHEMBL5864273
9.05	IC50	0.9	nM	CHEMBL6016114
9.05	IC50	0.9	nM	CHEMBL6030165
9.00	IC50	1	nM	CHEMBL5759650
8.96	IC50	1.1	nM	CHEMBL5799890
8.96	IC50	1.1	nM	CHEMBL5927332
8.92	IC50	1.2	nM	CHEMBL5791173
8.92	IC50	1.2	nM	CHEMBL5994885
8.92	IC50	1.2	nM	CHEMBL5800442
8.85	IC50	1.4	nM	CHEMBL5905450
8.85	IC50	1.4	nM	CHEMBL5761686
8.85	IC50	1.4	nM	CHEMBL5935744
8.85	IC50	1.4	nM	CHEMBL5792861
8.85	IC50	1.4	nM	CHEMBL5855363
8.85	IC50	1.4	nM	CHEMBL5980335
8.82	IC50	1.5	nM	CHEMBL5874970
8.82	IC50	1.5	nM	CHEMBL5845255
8.82	IC50	1.5	nM	CHEMBL5808988
8.80	IC50	1.6	nM	CHEMBL6058008
8.80	IC50	1.6	nM	CHEMBL5878735
8.77	IC50	1.7	nM	CHEMBL5813238
8.77	IC50	1.7	nM	CHEMBL5845911
8.74	IC50	1.8	nM	CHEMBL6057739
8.72	IC50	1.9	nM	CHEMBL5995142
8.72	IC50	1.9	nM	CHEMBL5885075
8.72	IC50	1.9	nM	CHEMBL5799890
8.70	IC50	2	nM	CHEMBL5768221
8.66	IC50	2.2	nM	CHEMBL5782929
8.66	IC50	2.2	nM	CHEMBL5954693
8.64	IC50	2.3	nM	CHEMBL5955965
8.62	IC50	2.4	nM	CHEMBL5924721
8.62	IC50	2.4	nM	CHEMBL5842848
8.59	IC50	2.6	nM	CHEMBL5780490
8.57	IC50	2.7	nM	CHEMBL5914671
8.57	IC50	2.7	nM	CHEMBL5782929
8.55	IC50	2.8	nM	CHEMBL5831559
8.55	IC50	2.8	nM	CHEMBL5825496
8.52	IC50	3	nM	CHEMBL5763157
8.48	IC50	3.3	nM	CHEMBL5784669
8.47	IC50	3.4	nM	CHEMBL5905450
8.47	IC50	3.4	nM	CHEMBL6053509
8.47	IC50	3.4	nM	CHEMBL5974903

PubChem BioAssay actives

181 with measured affinity, of 403 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
N-(2-hydroxyethyl)-3-(2,3,4-trichlorophenyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0050	uM
5-bromo-2-methoxy-N-quinolin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0060	uM
5-chloro-2-methoxy-N-quinolin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0060	uM
5-[(5-bromo-2-methoxyphenyl)sulfonylamino]pyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0140	uM
2,5-dimethoxy-N-quinolin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0150	uM
5-[(5-chloro-2-methoxyphenyl)sulfonylamino]pyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0160	uM
5-[(5-fluoro-2-methoxyphenyl)sulfonylamino]pyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0190	uM
5-chloro-2-methoxy-N-[5-(4-methoxyphenyl)-3-pyridinyl]benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0230	uM
2-methoxy-N-quinolin-3-yl-5-(trifluoromethyl)benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0260	uM
3-(2,4-dichlorophenyl)-N-(3-hydroxypropyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0310	uM
3-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0350	uM
3-(2,4-dichlorophenyl)-N-(4-hydroxybutyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0350	uM
5-cyano-2-methoxy-N-quinolin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0380	uM
5-bromo-2-methoxy-N-pyridin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0430	uM
3-(2,4-dichlorophenyl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0440	uM
3-(2,4-dichlorophenyl)-1H-pyrazole-5-carbohydrazide	411208: Inhibition of TNSALP	ic50	0.0440	uM
3-(2,4-dichlorophenyl)-N-(2-methoxyethyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0460	uM
3-(2,4-dichlorophenyl)-N,N-bis(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0470	uM
3-(2,4-dichlorophenyl)-N-propan-2-yl-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0510	uM
3-(2,4-dichloro-5-fluorophenyl)-N-(3-hydroxypropyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0560	uM
methyl 5-[(5-chloro-2-methoxyphenyl)sulfonylamino]pyridine-3-carboxylate	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0650	uM
5-chloro-2-methoxy-N-(5-pyridin-4-yl-3-pyridinyl)benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0730	uM
5-chloro-2-methoxy-N-(5-pyridin-3-yl-3-pyridinyl)benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0730	uM
2,5-dimethoxy-N-(5-pyridin-4-yl-3-pyridinyl)benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0730	uM
3-(2,4-dichlorophenyl)-N-(2-methylpropyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.0820	uM
5-chloro-2-methoxy-N-pyridin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.0840	uM
3-(2,4-dichloro-5-fluorophenyl)-N-(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.1000	uM
5-[(5-chloro-2-methoxyphenyl)sulfonylamino]-N-methylpyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1090	uM
3-(2,4-dichlorophenyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.1190	uM
2,5-dimethoxy-N-(5-pyridin-3-yl-3-pyridinyl)benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1200	uM
3-(2,4-dichloro-5-fluorophenyl)-N,N-bis(2-hydroxyethyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.1270	uM
5-[[2-methoxy-5-(trifluoromethoxy)phenyl]sulfonylamino]pyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1310	uM
5-[(5-chloro-2-methoxyphenyl)sulfonylamino]pyridine-3-carboxylic acid	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1340	uM
N-(2-hydroxyethyl)-3-(2,4,5-trifluorophenyl)-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.1340	uM
5-chloro-2-methoxy-N-[5-(4-methylphenyl)-3-pyridinyl]benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1470	uM
5-chloro-2-methoxy-N-[5-(3-methylphenyl)-3-pyridinyl]benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1600	uM
5-chloro-2-methoxy-N-[5-(2-methylphenyl)-3-pyridinyl]benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1780	uM
2-methoxy-N-pyridin-3-yl-5-(trifluoromethyl)benzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1830	uM
5-[(5-chloro-2-methoxyphenyl)sulfonylamino]-N-ethylpyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1930	uM
5-chloro-N-[5-(4-chlorophenyl)-3-pyridinyl]-2-methoxybenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.1980	uM
2-phenyl-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one	1402701: Inhibition of human TNAP expressed in COS7 cells preincubated for 5 to 7 mins followed by CDP-star substrate addition measured after 15 to 20 mins by luminescence assay	ic50	0.2100	uM
(3Z)-3-[(4-chlorophenyl)methylidene]-1,1-dioxo-1lambda6,2-benzothiazin-4-one	1422552: Inhibition of human TNAP expressed in African green monkey COS7 cell membranes using CDP-star as substrate pretreated for 5 to 10 mins followed by substrate addition and measured after 15 to 20 mins by spectrophotometric method	ic50	0.2500	uM
3-[2-[(E)-(3-nitrophenyl)methylideneamino]-1,3-thiazol-4-yl]chromen-2-one	2007823: Inhibition of human TNAP	ic50	0.2500	uM
2-(4-methoxyphenyl)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one	1402701: Inhibition of human TNAP expressed in COS7 cells preincubated for 5 to 7 mins followed by CDP-star substrate addition measured after 15 to 20 mins by luminescence assay	ic50	0.2800	uM
3-(2,4-dichlorophenyl)-N,N-diethyl-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.2850	uM
2-(prop-2-enylamino)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one	1402701: Inhibition of human TNAP expressed in COS7 cells preincubated for 5 to 7 mins followed by CDP-star substrate addition measured after 15 to 20 mins by luminescence assay	ic50	0.2900	uM
5-[(5-chloro-2-methoxyphenyl)sulfonylamino]-N-phenylpyridine-3-carboxamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.3100	uM
5-cyano-2-methoxy-N-pyridin-3-ylbenzenesulfonamide	1372334: Inhibition of TNAP (unknown origin) using PPi as substrate	ic50	0.3220	uM
3-(2,4-dichloro-5-fluorophenyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide	411208: Inhibition of TNSALP	ic50	0.3240	uM
2-(4-aminoanilino)-7-(trifluoromethyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one	1402701: Inhibition of human TNAP expressed in COS7 cells preincubated for 5 to 7 mins followed by CDP-star substrate addition measured after 15 to 20 mins by luminescence assay	ic50	0.3300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects binding, increases activity, affects cotreatment, decreases methylation, decreases activity (+1 more)	4
Dexamethasone	affects cotreatment, increases expression, decreases reaction, increases activity	4
Progesterone	decreases reaction, increases activity, decreases expression, affects cotreatment, increases expression	4
Tetrachlorodibenzodioxin	increases expression, affects expression, increases activity	4
sodium arsenite	affects methylation, decreases expression, increases expression	3
beta-glycerophosphoric acid	increases abundance, affects cotreatment, increases expression, increases activity, decreases reaction (+1 more)	3
Calcitriol	increases expression	3
Estradiol	affects binding, increases activity, affects cotreatment, increases expression, decreases reaction	3
Tobacco Smoke Pollution	affects expression, decreases methylation	3
Cadmium Chloride	decreases expression, decreases reaction, decreases activity, increases abundance	3
fenvalerate	decreases reaction, increases expression, increases activity	2
cobaltous chloride	decreases expression, increases reaction, affects reaction, increases expression	2
perfluorooctane sulfonic acid	affects expression, increases expression	2
8-prenylnaringenin	affects binding, increases activity, increases expression, decreases reaction	2
Fulvestrant	affects cotreatment, decreases methylation, affects binding, decreases reaction, increases activity	2
Acetaminophen	decreases expression	2
Arsenic	increases expression, decreases methylation, increases abundance	2
Ascorbic Acid	affects cotreatment, increases expression, decreases reaction	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Cadmium	increases abundance, decreases expression	2
Fluorides	increases expression, affects reaction, increases abundance	2
Hydrogen Peroxide	decreases activity, decreases expression, decreases reaction	2
Indomethacin	decreases expression, increases reaction, affects cotreatment, increases expression	2
Sodium Fluoride	increases abundance, increases expression, affects reaction	2
Tretinoin	decreases reaction, increases activity, increases degradation, decreases expression, increases expression (+1 more)	2
Valproic Acid	decreases methylation, increases expression	2
Cyclosporine	increases expression, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Permethrin	decreases reaction, increases expression, increases activity	2
alachlor	decreases reaction, increases expression	1

ChEMBL screening assays

58 unique, capped per target: 50 binding, 4 functional, 3 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1014656	Binding	Inhibition of TNSALP	Design and synthesis of pyrazole derivatives as potent and selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP). — Bioorg Med Chem Lett
CHEMBL1738602	Functional	PUBCHEM_BIOASSAY: Dose Response confirmation of uHTS inhibitors of Mouse Intestinal Alkaline Phosphatase using Tissue Nonspecific Alkaline Phosphatase. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID2806, AID2	PubChem BioAssay data set
CHEMBL3999775	ADMET	Drug metabolism assessed as alkaline phosphatase (unknown origin)-mediated (S)-3-hydroxypropyl 6-chloro-4-(1-cyclopropylethyl)-3-oxo-3,4-dihydropyrazin-2-yl(2,6-dichloro-4-(difluoromethoxy)phenyl)carbamate formation after 120 mins by LC-MS	Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability. — Bioorg Med Chem Lett

Cellosaurus cell lines

21 cell lines: 9 induced pluripotent stem cell, 9 finite cell line, 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0ZH	UOMi007-A	Induced pluripotent stem cell	Male
CVCL_C0ZI	UOMi008-A	Induced pluripotent stem cell	Male
CVCL_C3MJ	UOMi009-A	Induced pluripotent stem cell	Male
CVCL_C9VA	HPS2030	Induced pluripotent stem cell	Female
CVCL_C9VB	HPS2031	Induced pluripotent stem cell	Female
CVCL_C9VC	HPS2032	Induced pluripotent stem cell	Female
CVCL_C9VD	HPS2033	Induced pluripotent stem cell	Female
CVCL_C9VE	HPS2034	Induced pluripotent stem cell	Female
CVCL_C9VF	HPS2035	Induced pluripotent stem cell	Female
CVCL_DX14	HAP1 ALPL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02531867	PHASE4	COMPLETED	Post-approval Clinical Study of Asfotase Alfa Treatment for Patients With Hypophosphatasia (HPP) in Japan
NCT04189315	PHASE4	WITHDRAWN	Relieving Burden of Hypophosphatasia in Adults With Functional Impairment Due to Chronic Disease
NCT06015750	PHASE4	WITHDRAWN	Mitigate Immune-Mediated Loss of Therapeutic Response to Asfotase Alfa (STRENSIQ®) for Hypophosphatasia
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
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NCT06079372	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study of ALXN1850 in Pediatric Participants With HPP Previously Treated With Asfotase Alfa
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