ADAM17

Summary

ADAM17 (ADAM metallopeptidase domain 17, HGNC:195) is a protein-coding gene on chromosome 2p25.1, encoding Disintegrin and metalloproteinase domain-containing protein 17 (P78536). Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins including adhesion proteins, growth factor precursors and cytokines important for inflammation and immunity.

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands, and plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn’s disease patients, suggesting that the encoded protein may play a role in autoimmune disease. Additionally, this protease may play a role in viral infection through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2.

Source: NCBI Gene 6868 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inflammatory skin and bowel disease, neonatal, 1 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 626 total — 21 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:195
Approved symbol	ADAM17
Name	ADAM metallopeptidase domain 17
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	cSVP, CD156B
Ensembl gene	ENSG00000151694
Ensembl biotype	protein_coding
OMIM	603639
Entrez	6868

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 10 protein_coding, 9 retained_intron, 9 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000310823, ENST00000478059, ENST00000618923, ENST00000647610, ENST00000647622, ENST00000647979, ENST00000648002, ENST00000648548, ENST00000648857, ENST00000649068, ENST00000649227, ENST00000649686, ENST00000649798, ENST00000649972, ENST00000650116, ENST00000650241, ENST00000699315, ENST00000699316, ENST00000699317, ENST00000699318, ENST00000699319, ENST00000699320, ENST00000699321, ENST00000699322, ENST00000699323, ENST00000699324, ENST00000699325, ENST00000699326, ENST00000867642, ENST00000926352, ENST00000945282, ENST00000945283, ENST00000945284

RefSeq mRNA: 3 — MANE Select: NM_003183 NM_001382777, NM_001382778, NM_003183

CCDS: CCDS1665

Canonical transcript exons

ENST00000310823 — 19 exons

Exon	Start	End
ENSE00001001233	9497114	9497248
ENSE00001001234	9505166	9505365
ENSE00001001237	9509979	9510131
ENSE00001001241	9493747	9493825
ENSE00001001242	9502173	9502276
ENSE00001001249	9491101	9491151
ENSE00001001250	9494637	9494767
ENSE00001070592	9526111	9526244
ENSE00001070593	9527786	9527954
ENSE00001070595	9518103	9518247
ENSE00001070597	9517901	9517989
ENSE00001070599	9521203	9521316
ENSE00001070603	9523249	9523338
ENSE00001367317	9488486	9490518
ENSE00001490117	9492898	9492986
ENSE00003601365	9535834	9535922
ENSE00003645947	9536698	9536828
ENSE00003683390	9543153	9543285
ENSE00003832687	9555509	9555830

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 95.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.8164 / max 319.7694, expressed in 1814 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26831	20.0720	1806
26829	1.5219	799
26832	0.9300	562
26828	0.6588	259
26830	0.5111	246
26817	0.1225	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.24	gold quality
adrenal tissue	UBERON:0018303	93.53	gold quality
calcaneal tendon	UBERON:0003701	93.49	gold quality
pericardium	UBERON:0002407	93.40	gold quality
monocyte	CL:0000576	93.34	gold quality
tendon	UBERON:0000043	93.29	gold quality
tendon of biceps brachii	UBERON:0008188	93.05	gold quality
sural nerve	UBERON:0015488	93.01	gold quality
lower lobe of lung	UBERON:0008949	92.82	gold quality
mononuclear cell	CL:0000842	92.79	gold quality
leukocyte	CL:0000738	92.39	gold quality
right lung	UBERON:0002167	92.18	gold quality
oviduct epithelium	UBERON:0004804	91.53	gold quality
gall bladder	UBERON:0002110	91.01	gold quality
upper lobe of lung	UBERON:0008948	90.92	gold quality
cartilage tissue	UBERON:0002418	90.86	gold quality
upper lobe of left lung	UBERON:0008952	90.80	gold quality
ventricular zone	UBERON:0003053	90.77	gold quality
left ovary	UBERON:0002119	90.53	gold quality
secondary oocyte	CL:0000655	90.51	gold quality
mammalian vulva	UBERON:0000997	90.49	gold quality
lung	UBERON:0002048	90.49	gold quality
stromal cell of endometrium	CL:0002255	90.45	gold quality
right ovary	UBERON:0002118	90.32	gold quality
corpus callosum	UBERON:0002336	90.28	gold quality
synovial joint	UBERON:0002217	90.06	gold quality
epithelium of mammary gland	UBERON:0003244	89.97	gold quality
bone marrow cell	CL:0002092	89.79	gold quality
ovary	UBERON:0000992	89.72	gold quality
mammary duct	UBERON:0001765	89.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMAL1, ESR1, HIF1A, NFKB, SOX9, SP1

Literature-anchored findings (GeneRIF, showing 40)

• Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme (PMID:11988096)
• phosphorylated by ERKs; demonstrates a potential role in regulated shedding of membrane proteins (PMID:12058067)
• Data show that tumor necrosis factor-alpha-converting enzyme (TACE)is involved in the shedding of L-selectin by NSAIDS in human neutrophils. (PMID:12147693)
• regulated by protein tyrosine phosphatase PTPH1 (PMID:12207026)
• This enzyme mediates MUC1 shedding. (PMID:12441351)
• multiple sclerosis patients found positive for TACE mRNA in PBMCs showed a significantly higher mean number of new lesions (PMID:12474981)
• The results indicate that ADAM9, ADAM10, and ADAM17, members of the disintegrin and metalloprotease family, catalyze alpha-secretory cleavage and therefore act as alpha-secretases in A172 cells. (PMID:12535668)
• Review. The activation of EGFR in response to smoke involves cleavage of amphiregulin by ADAM 17. (PMID:12568494)
• Data show that tumor necrosis factor-alpha converting enzyme (TACE) is required for epidermal growth factor receptor activation in vivo and for the development of tumors in nude mice, indicating a crucial role of TACE in tumorigenesis. (PMID:12606576)
• TACE binds to SAP97, which may have a role in the regulation of TACE shedding activity (PMID:12668732)
• Intracellular maturation and transport of TACE. (PMID:12706122)
• ADAM-17 has a role in stimulation of lung epithelial cells upon exposure to tobacco smoke by cleaving amphiregulin, which binds to EGF receptor (PMID:12711607)
• TACE has a role in protein ectodomain shedding (PMID:12714588)
• under inflammatory conditions, ADAM-10, expressed by perivascular macrophages, and ADAM-17, expressed by invading T cells, may actively contribute to the pathogenesis of inflammatory disorders of the CNS. (PMID:12730960)
• Data show that in squamous cell carcinoma cells, stimulation with G protein-coupled receptor agonists specifically results in cleavage and release of amphiregulin (AR) by TACE. (PMID:12743035)
• Tumor necrosis factor-alpha converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation (PMID:12755693)
• Membrane-anchored CD40 is processed by the tumor necrosis factor-alpha-converting enzyme. Implications for CD40 signaling. (PMID:12810728)
• cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (PMID:12832423)
• TACE (ADAM 17) may not be the ectoprotease involved in the secretion of pro-EGF ectodomain (PMID:12947092)
• role in mucin production by airway epithelial cells by means of a TACE ligand-epidermal growth factor receptor cascade in response to various stimuli (PMID:12972643)
• ADAM-17/TACE and TIMP-3 might play an important role in the pathogenesis of prostate cancer (PMID:14532978)
• TACE controls mast cell survival by regulating shedding and surface expression of c-Kit (PMID:14625290)
• Integrin alpha5beta1 and ADAM-17 interact in vitro and co-localize in migrating HeLa cells (PMID:14970227)
• ADAM-17 IS a potent activator of Vibrio Cholerae pro-cytolysin. (PMID:15066987)
• although there is a seemingly high structural similarity between TACE and MMP-2, these enzymes are significantly diverse in the electronic and chemical properties within their active sites (PMID:15102849)
• ADAM10 is the major alpha-secretase cleaving amyloid precursor protein, with TACE playing a minor role; neither ADAM10 nor TACE is involved in the shedding of angiotensin converting enzyme (PMID:15182369)
• analysis of the molecular basis of the inactivity of tissue inhibitor of metalloproteinase-2 against tumor necrosis factor-alpha-converting enzyme (PMID:15308656)
• Lower mRNA expression of ADAM17 mRNA in solitary large cell hepatocellular carcinoma may be associated with the better molecular pathological features. (PMID:15309730)
• Data show that activation of ADAM-17 results in discrete cellular responses, while G protein-coupled receptor agonists promote activation of the Ras/MAPK pathway and cell proliferation via the epidermal growth factor receptor. (PMID:15337756)
• GPV is cleaved upon agonist-induced platelet activation, with ADAM17 as the major enzyme mediating this process (PMID:15691827)
• the active form of TACE is overexpressed in breast tumors and may indicate that TACE is responsible for Nectin-4 shedding not only in vitro but also in vivo (PMID:15784625)
• ADAM17 is the protease responsible for shedding of the SARS-CoV receptor, ACE2 (PMID:15983030)
• Bacteria are physiological activators of TACE expression, which provides a mechanism to regulate inflammatory signaling that is initiated by airway epithelial cells. (PMID:16034137)
• TIMP-3 reactive site mutations disrupt inhibition of matrix metalloproteinases but not TACE (PMID:16079149)
• HNE activates TACE via ROS generation, resulting in cleavage of pro-TGF-alpha, EGFR activation, and MUC5AC mucin expression in airway epithelial cells (PMID:16148149)
• GPIbalpha and GPV are shed through an ADAM17-dependent mechanism after aspirin administration (PMID:16179345)
• the expression, regulation, and catalytic function of TACE in healthy human alveolar macrophages (PMID:16210695)
• These data show that inhibition of TNF-alpha processing by acute ethanol is a direct affect of ethanol on the cell membrane and is reversible upon cessation or metabolism. (PMID:16246259)
• Overexpression of TACE in HEK293 cells increased the release of soluble APLP2 severalfold. (PMID:16279945)
• analysis of how TACE mediates the ectodomain cleavage of ICAM-1 (PMID:16332693)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam17a	ENSDARG00000043213
danio_rerio	adam17b	ENSDARG00000093093
mus_musculus	Adam17	ENSMUSG00000052593
rattus_norvegicus	Adam17	ENSRNOG00000060694
drosophila_melanogaster	Tace	FBGN0039734
caenorhabditis_elegans		WBGENE00000075

Paralogs (20): ADAM22 (ENSG00000008277), ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM10 (ENSG00000137845), ADAM21 (ENSG00000139985), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 17 — P78536 (reviewed: P78536)

Alternative names: Snake venom-like protease, TNF-alpha convertase, TNF-alpha-converting enzyme

All UniProt accessions (13): P78536, A0A3B3ISQ1, A0A3B3IST4, A0A3B3ITB5, A0A3B3ITW9, A0A8V8TN27, A0A8V8TNK2, A0A8V8TNK7, A0A8V8TPG8, A0A8V8TPV7, A6H8L4, A8K1B4, B2RNB2

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins including adhesion proteins, growth factor precursors and cytokines important for inflammation and immunity. Cleaves the membrane-bound precursor of TNF to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2. Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain. Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3. Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R. Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells. Cleaves TREM2, resulting in shedding of the TREM2 ectodomain.

Subunit / interactions. Interacts with MAD2L1, MAPK14 and MUC1. Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2. Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2. Interacts with TSPAN8.

Subcellular location. Cell membrane.

Tissue specificity. Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. Expressed in natural killer cells (at protein level).

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at Thr-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding.

Disease relevance. Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328] A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

Induction. In arthritis-affected cartilage.

Isoforms (2)

UniProt ID	Names	Canonical?
P78536-1	A	yes
P78536-2	B

RefSeq proteins (3): NP_001369706, NP_001369707, NP_003174* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001590	Peptidase_M12B	Domain
IPR001762	Disintegrin_dom	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR032029	ADAM17_MPD	Domain
IPR034025	ADAM10_ADAM17	Domain
IPR036436	Disintegrin_dom_sf	Homologous_superfamily
IPR051489	ADAM_Metalloproteinase	Family

Pfam: PF00200, PF13574, PF16698

Enzyme classification (BRENDA):

• EC 3.4.24.86 — ADAM 17 endopeptidase (BRENDA: 9 organisms, 301 substrates, 622 inhibitors, 18 Km, 17 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
(EDANS)-EPLAQAVRSSSK-(DABCYL)	0.0034–0.012	4
S80-GLYCOSYLATED (EDANS)-EPLAQAVRSSSK-(DABCYL)	0.003–0.01	4
(EDANS)-ELAQAVRSSSRK-(DABCYL)	0.0072–0.016	2
S80-GLYCOSYLATED (EDANS)-ELAQAVRSSSRK-(DABCYL)	0.0076–0.068	2
ABZ-ASN-TYR-MET-ALA-LEU-ARG-ARG-DAP(DNP)-NH2	0.0223	1
ABZ-ASN-TYR-MET-ALA-LEU-ARG-ARG-LYS(DNP)-NH2	0.0161	1
ABZ-ASN-TYR-MET-ALA-LEU-ARG-ARG-TYR(3-NO2)-NH2	0.0227	1
GLU(EDANS)-PRO-LEU-ALA-GLN-ALA-VAL-ARG-SER-SER(4	0.003	1
GLU(EDANS)-PRO-LEU-ALA-GLN-ALA-VAL-ARG-SER-SER-S	0.012	1
NH2-LAQAVRSSSR-OH	1.3	1

UniProt features (124 total): strand 45, helix 21, glycosylation site 9, turn 8, disulfide bond 7, modified residue 5, compositionally biased region 4, binding site 4, sequence conflict 4, short sequence motif 3, topological domain 2, sequence variant 2, domain 2, region of interest 2, signal peptide 1, propeptide 1, active site 1, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

33 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2DDF	X-RAY DIFFRACTION	1.7
8CQY	X-RAY DIFFRACTION	1.7
3L0V	X-RAY DIFFRACTION	1.75
3EWJ	X-RAY DIFFRACTION	1.8
3KMC	X-RAY DIFFRACTION	1.8
3KME	X-RAY DIFFRACTION	1.85
3LE9	X-RAY DIFFRACTION	1.85
3O64	X-RAY DIFFRACTION	1.88
2I47	X-RAY DIFFRACTION	1.9
3E8R	X-RAY DIFFRACTION	1.9
3EDZ	X-RAY DIFFRACTION	1.9
3LGP	X-RAY DIFFRACTION	1.9
3L0T	X-RAY DIFFRACTION	1.92
1BKC	X-RAY DIFFRACTION	2
2OI0	X-RAY DIFFRACTION	2
3B92	X-RAY DIFFRACTION	2
3LEA	X-RAY DIFFRACTION	2
2FV9	X-RAY DIFFRACTION	2.02
2FV5	X-RAY DIFFRACTION	2.1
3G42	X-RAY DIFFRACTION	2.1
1ZXC	X-RAY DIFFRACTION	2.28
2A8H	X-RAY DIFFRACTION	2.3
3CKI	X-RAY DIFFRACTION	2.3
8SNN	ELECTRON MICROSCOPY	2.32
8SNL	ELECTRON MICROSCOPY	2.78
8SNO	ELECTRON MICROSCOPY	2.78
9XY4	ELECTRON MICROSCOPY	3.12
9E6K	ELECTRON MICROSCOPY	3.15
9Q7Y	ELECTRON MICROSCOPY	3.35
9O54	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78536-F1	72.72	0.25

Antibody-complex structures (SAbDab): 3 — 9E6K, 9O54, 9O58

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): 406

Ligand- & substrate-binding residues (4): 184 (in inhibited form); 405; 409; 415

Post-translational modifications (5): 735, 761, 767, 791, 819

Disulfide bonds (7): 225–333, 365–469, 423–453, 534–555, 573–582, 578–591, 593–600

Glycosylation sites (9): 103, 157, 174, 264, 452, 498, 539, 551, 594

Function

Pathways and Gene Ontology

Reactome pathways

38 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1442490	Collagen degradation
R-HSA-177929	Signaling by EGFR
R-HSA-193692	Regulated proteolysis of p75NTR
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2660826	Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-5362798	Release of Hh-Np from the secreting cell
R-HSA-75893	TNF signaling
R-HSA-9662834	CD163 mediating an anti-inflammatory response
R-HSA-982772	Growth hormone receptor signaling
R-HSA-1236394	Signaling by ERBB4
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-1980143	Signaling by NOTCH1
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2660825	Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5358351	Signaling by Hedgehog

MSigDB gene sets: 546 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_CELLULAR_RESPONSE_TO_LIPOPROTEIN_PARTICLE_STIMULUS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, MODULE_416, REACTOME_SIGNALING_BY_NOTCH, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, chr2p25, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_T_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (47): response to hypoxia (GO:0001666), neutrophil mediated immunity (GO:0002446), germinal center formation (GO:0002467), production of molecular mediator involved in inflammatory response (GO:0002532), positive regulation of leukocyte chemotaxis (GO:0002690), proteolysis (GO:0006508), membrane protein ectodomain proteolysis (GO:0006509), cell adhesion (GO:0007155), epidermal growth factor receptor signaling pathway (GO:0007173), Notch signaling pathway (GO:0007219), Notch receptor processing (GO:0007220), positive regulation of cell population proliferation (GO:0008284), response to xenobiotic stimulus (GO:0009410), positive regulation of T cell chemotaxis (GO:0010820), negative regulation of neuron projection development (GO:0010977), protein processing (GO:0016485), signal release (GO:0023061), B cell differentiation (GO:0030183), positive regulation of cell growth (GO:0030307), positive regulation of cell migration (GO:0030335), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), response to lipopolysaccharide (GO:0032496), positive regulation of chemokine production (GO:0032722), positive regulation of tumor necrosis factor production (GO:0032760), regulation of mast cell apoptotic process (GO:0033025), T cell differentiation in thymus (GO:0033077), cell adhesion mediated by integrin (GO:0033627), wound healing, spreading of epidermal cells (GO:0035313), ERBB2-EGFR signaling pathway (GO:0038134), amyloid precursor protein catabolic process (GO:0042987), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), spleen development (GO:0048536), regulation of axon regeneration (GO:0048679), cell motility (GO:0048870), defense response to Gram-positive bacterium (GO:0050830), cellular response to high density lipoprotein particle stimulus (GO:0071403), commissural neuron axon guidance (GO:0071679), negative regulation of cold-induced thermogenesis (GO:0120163)

GO Molecular Function (16): endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), Notch binding (GO:0005112), interleukin-6 receptor binding (GO:0005138), integrin binding (GO:0005178), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), SH3 domain binding (GO:0017124), cytokine binding (GO:0019955), PDZ domain binding (GO:0030165), tumor necrosis factor binding (GO:0043120), metal ion binding (GO:0046872), metallodipeptidase activity (GO:0070573), metalloendopeptidase activity involved in amyloid precursor protein catabolic process (GO:1902945), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (13): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), endoplasmic reticulum lumen (GO:0005788), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), actin cytoskeleton (GO:0015629), membrane (GO:0016020), apical plasma membrane (GO:0016324), membrane raft (GO:0045121), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), ruffle membrane (GO:0032587)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signaling by ERBB4	1
Degradation of the extracellular matrix	1
p75 NTR receptor-mediated signalling	1
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Hedgehog ligand biogenesis	1
Death Receptor Signaling	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Cytokine Signaling in Immune system	1
Immune System	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein metabolic process	2
positive regulation of cellular process	2
peptidase activity	2
signaling receptor binding	2
protein domain specific binding	2
response to stress	1
response to decreased oxygen levels	1
myeloid leukocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
anatomical structure formation involved in morphogenesis	1
inflammatory response	1
multicellular organismal process	1
positive regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
leukocyte chemotaxis	1
positive regulation of chemotaxis	1
membrane protein proteolysis	1
cellular process	1
ERBB signaling pathway	1
cell surface receptor signaling pathway	1
cell population proliferation	1
regulation of cell population proliferation	1
response to chemical	1
T cell chemotaxis	1
regulation of T cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
positive regulation of T cell migration	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
proteolysis	1
protein maturation	1
cell-cell signaling	1
secretion by cell	1
lymphocyte differentiation	1
B cell activation	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1

Protein interactions and networks

STRING

2775 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM17	TIMP3	P35625	947
ADAM17	TMPRSS2	O15393	937
ADAM17	RHBDF2	Q6PJF5	931
ADAM17	ACE2	Q9BYF1	885
ADAM17	SELL	P14151	853
ADAM17	ACE	P12821	815
ADAM17	TNF	P01375	811
ADAM17	TGFA	P01135	803
ADAM17	FURIN	P09958	767
ADAM17	RHBDF1	Q96CC6	753
ADAM17	CX3CL1	P78423	741
ADAM17	TIMP1	P01033	724
ADAM17	CXCL16	Q9H2A7	715
ADAM17	KL	Q9UEF7	708
ADAM17	PSEN1	P49768	703

IntAct

190 interactions, top by confidence:

A	B	Type	Score
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
ADAM17	DLG1	psi-mi:“MI:0407”(direct interaction)	0.740
DLG1	ADAM17	psi-mi:“MI:0407”(direct interaction)	0.740
ADAM17	DLG1	psi-mi:“MI:0915”(physical association)	0.740
DLG1	ADAM17	psi-mi:“MI:0915”(physical association)	0.740
ADAM17	DLG1	psi-mi:“MI:0403”(colocalization)	0.740
DLG1	ADAM17	psi-mi:“MI:0403”(colocalization)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CD9	ITGB1	psi-mi:“MI:0914”(association)	0.690
CA10	WDHD1	psi-mi:“MI:0914”(association)	0.640
ITGB1	ADAM17	psi-mi:“MI:0915”(physical association)	0.610
ADAM17	ITGB1	psi-mi:“MI:0407”(direct interaction)	0.610
ADAM17	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.590
PTPN3	ADAM17	psi-mi:“MI:0915”(physical association)	0.590
MAD2L1	ADAM17	psi-mi:“MI:0915”(physical association)	0.580
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530

BioGRID (175): ADAM17 (Affinity Capture-MS), ADAM17 (Affinity Capture-MS), ADAM17 (Co-localization), DLG1 (Two-hybrid), ADAM17 (Proximity Label-MS), DLG1 (Reconstituted Complex), DLG1 (Affinity Capture-Western), ADAM17 (Affinity Capture-Western), ADAM17 (Affinity Capture-Western), ADAM17 (Co-localization), SDK2 (Affinity Capture-MS), ADAM17 (Affinity Capture-MS), ADAM17 (Affinity Capture-MS), ADAM17 (Affinity Capture-MS), LRRC3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D0C023, A5Z1X6, B0FYY4, C0K3N4, D3GGZ8, D5FM37, G5ECE3, G5ECS8, G5EGM1, O18016, O64758, O73682, O76840, O77469, O77636, P08479, P0DRJ0, P11584, P24348, P33434, P33436, P49134, P53712, P78536, P81439, P84032, P98060, P98092, Q00174, Q04833, Q06561, Q11101, Q19204, Q19267, Q21313, Q27591, Q7Z1K3, Q811M5, Q8L7E3, Q8R4U0

Diamond homologs: A0A0B4U9L8, A3R0T9, A4PBQ9, A8QL48, A8QL49, A8QL59, B8K1W0, C5FUK3, C5H5D1, C5H5D2, C5H5D3, C5H5D4, C5H5D5, C5H5D6, C9E1R7, C9E1R8, C9E1S0, D3TTC2, D8VNS0, F8S108, G5EFD5, J3S829, J3S830, J3SDW6, J3SDW8, O13766, O35227, O35674, O42138, O43184, O73795, O77636, O88839, O93523, P0C6B6, P0C7B0, P0DM87, P0DM89, P0DM90, P0DM97

SIGNOR signaling

24 interactions.

A	Effect	B	Mechanism
ADAM17	up-regulates	EGFR
ADAM17	“up-regulates activity”	NOTCH	cleavage
ADAM17	“up-regulates activity”	TGFA	cleavage
ADAM17	“up-regulates activity”	AREG	cleavage
ADAM17	“up-regulates activity”	EREG	cleavage
ADAM17	“up-regulates activity”	HBEGF	cleavage
ADAM17	“down-regulates activity”	GP1BA	cleavage
GPR50	“up-regulates activity”	ADAM17	binding
SRC	“up-regulates activity”	ADAM17	phosphorylation
hsa-mir-145-5p	“down-regulates quantity by repression”	ADAM17	“post transcriptional regulation”
hsa-miR-148a-3p	“down-regulates quantity by repression”	ADAM17	“post transcriptional regulation”
hsa-mir-152-3p	“down-regulates quantity by repression”	ADAM17	“post transcriptional regulation”
hsa-miR-338-3p	“down-regulates quantity by repression”	ADAM17	“post transcriptional regulation”
hsa-mir-708-3p	“down-regulates quantity by repression”	ADAM17	“post transcriptional regulation”
hsa-mir-224-5p	“down-regulates quantity by repression”	ADAM17	“post transcriptional regulation”
ADAM17	“up-regulates quantity”	TNF	cleavage
ADAM17	“up-regulates activity”	NOTCH1	cleavage
ERK1/2	up-regulates	ADAM17	phosphorylation
MAPK3	up-regulates	ADAM17	phosphorylation
ADAM17	down-regulates	MUC1	cleavage
ADAM17	up-regulates	NOTCH	cleavage
MAPK14	“up-regulates activity”	ADAM17	phosphorylation
ADAM17	“up-regulates activity”	APP	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 150 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	6	34.3×	2e-06
Long-term potentiation	7	33.3×	2e-07
Unblocking of NMDA receptors, glutamate binding and activation	6	32.6×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	6	32.6×	2e-06
Assembly and cell surface presentation of NMDA receptors	10	25.4×	3e-09
Neurexins and neuroligins	10	19.7×	2e-08
Protein-protein interactions at synapses	6	15.9×	2e-04
Non-integrin membrane-ECM interactions	6	9.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
plasma membrane tubulation	6	48.9×	3e-07
establishment or maintenance of epithelial cell apical/basal polarity	11	46.3×	2e-13
receptor clustering	8	36.2×	1e-08
protein localization to synapse	6	33.3×	3e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	7	25.1×	2e-06
maintenance of blood-brain barrier	5	17.4×	8e-04
cell-cell adhesion	16	11.8×	2e-10
protein-containing complex assembly	11	9.1×	6e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	9
Uncertain significance	244
Likely benign	261
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1452811	NM_003183.6(ADAM17):c.1467_1468del (p.Cys489_Asp490delinsTer)	Pathogenic
1459451	NM_003183.6(ADAM17):c.987_988dup (p.Ser330fs)	Pathogenic
2092587	NM_003183.6(ADAM17):c.619+1del	Pathogenic
2424648	NC_000002.11:g.(?9645275)(9650280_?)del	Pathogenic
2424649	NC_000002.11:g.(?9663358)(9666393_?)del	Pathogenic
2426587	NC_000002.11:g.(?7968276)(10192634_?)del	Pathogenic
2745572	NM_003183.6(ADAM17):c.1305_1306del (p.Met435fs)	Pathogenic
2767335	NC_000002.12:g.9523337_9523340del	Pathogenic
2812323	NM_003183.6(ADAM17):c.1151del (p.Gly383_Leu384insTer)	Pathogenic
2830713	NM_003183.6(ADAM17):c.1015dup (p.Thr339fs)	Pathogenic
30374	NM_003183.6(ADAM17):c.603_606del (p.Asp201fs)	Pathogenic
3062591	GRCh37/hg19 2p25.2-24.1(chr2:6375088-23538518)x3	Pathogenic
3255337	NM_003183.6(ADAM17):c.308dup (p.Asn103fs)	Pathogenic
3610015	NM_003183.6(ADAM17):c.631C>T (p.Arg211Ter)	Pathogenic
3661120	NM_003183.6(ADAM17):c.1352C>G (p.Ser451Ter)	Pathogenic
4690236	ADAM17, ASP647ASN	Pathogenic
4766309	NM_003183.6(ADAM17):c.714C>A (p.Tyr238Ter)	Pathogenic
60105	GRCh38/hg38 2p25.2-24.3(chr2:6531172-16103799)x1	Pathogenic
640542	NM_003183.6(ADAM17):c.1645del (p.Thr549fs)	Pathogenic
852789	NM_003183.6(ADAM17):c.1975_1993+4del	Pathogenic
857427	NM_003183.6(ADAM17):c.1793dup (p.Asn598fs)	Pathogenic
1705353	NM_003183.6(ADAM17):c.1344+1G>A	Likely pathogenic
2101430	NM_003183.6(ADAM17):c.1544+2T>C	Likely pathogenic
2831726	NM_003183.6(ADAM17):c.1344+1G>T	Likely pathogenic
2853995	NM_003183.6(ADAM17):c.361+1G>C	Likely pathogenic
4291994	NM_003183.6(ADAM17):c.1930C>T (p.Arg644Ter)	Likely pathogenic
4293786	NM_003183.6(ADAM17):c.769dup (p.Arg257fs)	Likely pathogenic
4530828	NM_003183.6(ADAM17):c.450G>A (p.Glu150=)	Likely pathogenic
4720642	NM_003183.6(ADAM17):c.843+1G>A	Likely pathogenic
985573	NM_003183.6(ADAM17):c.230+1G>A	Likely pathogenic

SpliceAI

3462 predictions. Top by Δscore:

Variant	Effect	Δscore
2:9490515:CGTT:C	acceptor_gain	1.0000
2:9490517:TT:T	acceptor_gain	1.0000
2:9490517:TTC:T	acceptor_loss	1.0000
2:9490518:TC:T	acceptor_loss	1.0000
2:9490519:C:CC	acceptor_gain	1.0000
2:9490520:T:A	acceptor_loss	1.0000
2:9492897:CCACA:C	donor_gain	1.0000
2:9492982:CTTTC:C	acceptor_gain	1.0000
2:9493743:CTA:C	donor_loss	1.0000
2:9493744:TACCA:T	donor_loss	1.0000
2:9493745:A:AC	donor_gain	1.0000
2:9493745:ACCAA:A	donor_loss	1.0000
2:9493746:C:CC	donor_gain	1.0000
2:9493765:G:C	donor_gain	1.0000
2:9493821:TTGCC:T	acceptor_gain	1.0000
2:9493822:TGCC:T	acceptor_gain	1.0000
2:9493822:TGCCC:T	acceptor_loss	1.0000
2:9493823:GCC:G	acceptor_gain	1.0000
2:9493824:CC:C	acceptor_gain	1.0000
2:9493824:CCC:C	acceptor_gain	1.0000
2:9493825:CC:C	acceptor_gain	1.0000
2:9493826:C:CC	acceptor_gain	1.0000
2:9493826:C:T	acceptor_gain	1.0000
2:9493826:CTAT:C	acceptor_loss	1.0000
2:9493828:A:AC	acceptor_gain	1.0000
2:9493828:A:C	acceptor_gain	1.0000
2:9494631:AC:A	donor_loss	1.0000
2:9494632:CTCA:C	donor_loss	1.0000
2:9494633:T:TG	donor_loss	1.0000
2:9494634:CA:C	donor_loss	1.0000

AlphaMissense

5521 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:9492930:A:G	W684R	1.000
2:9492930:A:T	W684R	1.000
2:9493818:C:G	C641S	1.000
2:9493819:A:G	C641R	1.000
2:9493819:A:T	C641S	1.000
2:9494647:C:G	C635S	1.000
2:9494647:C:T	C635Y	1.000
2:9494648:A:T	C635S	1.000
2:9494661:A:C	C630W	1.000
2:9494662:C:A	C630F	1.000
2:9494662:C:G	C630S	1.000
2:9494662:C:T	C630Y	1.000
2:9494663:A:G	C630R	1.000
2:9494663:A:T	C630S	1.000
2:9494752:C:G	C600S	1.000
2:9494752:C:T	C600Y	1.000
2:9494753:A:G	C600R	1.000
2:9494753:A:T	C600S	1.000
2:9497152:C:G	C582S	1.000
2:9497152:C:T	C582Y	1.000
2:9497153:A:T	C582S	1.000
2:9497164:C:G	C578S	1.000
2:9497165:A:G	C578R	1.000
2:9497165:A:T	C578S	1.000
2:9497179:C:G	C573S	1.000
2:9497180:A:T	C573S	1.000
2:9497196:G:C	C567W	1.000
2:9497197:C:G	C567S	1.000
2:9497198:A:G	C567R	1.000
2:9497198:A:T	C567S	1.000

dbSNP variants (sampled 300 via entrez): RS1000027531 (2:9555351 A>G), RS1000050918 (2:9518216 G>GAT), RS1000135630 (2:9533796 A>G), RS1000167102 (2:9524174 G>C), RS1000208470 (2:9514861 C>A,T), RS1000351480 (2:9504245 G>A), RS1000364225 (2:9531237 C>G,T), RS1000365431 (2:9501595 A>G), RS1000376624 (2:9501303 A>G), RS1000419260 (2:9552376 A>C), RS1000455203 (2:9552082 G>A), RS1000557772 (2:9554600 C>G,T), RS1000642804 (2:9507585 C>A,T), RS1000740160 (2:9498527 G>A), RS1000794076 (2:9546306 T>C)

Disease associations

OMIM: gene MIM:603639 | disease phenotypes: MIM:614328, MIM:621490

GenCC curated gene-disease

Disease	Classification	Inheritance
inflammatory skin and bowel disease, neonatal, 1	Definitive	Autosomal recessive
neonatal inflammatory skin and bowel disease	Supportive	Autosomal recessive
congenital heart disease	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Limited	AD

Mondo (4): inflammatory skin and bowel disease, neonatal, 1 (MONDO:0013693), neonatal inflammatory skin and bowel disease (MONDO:0017411), hypotrichosis 16 (MONDO:0980972), congenital heart disease (MONDO:0005453)

Orphanet (2): Neonatal erythroderma-autoinflammation-inflammatory bowel disease syndrome (Orphanet:294023), Microphthalmia-anophthalmia-coloboma (Orphanet:98555)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000498	Blepharitis
HP:0001019	Erythroderma
HP:0001508	Failure to thrive
HP:0001712	Left ventricular hypertrophy
HP:0001805	Onychogryphosis
HP:0001818	Paronychia
HP:0003212	Increased circulating IgE concentration
HP:0003765	Psoriasiform dermatitis
HP:0005406	Recurrent bacterial skin infections
HP:0008396	Chronic monilial nail infection
HP:0010783	Erythema
HP:0011131	Perianal dermatitis
HP:0011228	Horizontal eyebrow
HP:0011354	Generalized abnormality of skin
HP:0011473	Villous atrophy
HP:0012390	Anal fissure
HP:0025085	Bloody diarrhea
HP:0031123	Recurrent gastroenteritis
HP:0033117	Duodenitis
HP:0033194	Perioral erythema
HP:0033195	Perianal erythema
HP:0040181	Chapped lip
HP:0040189	Scaling skin
HP:0100038	Slow-growing scalp hair
HP:0200039	Pustule
HP:0410017	Otitis externa

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST008362_98	Birth weight	2.000000e-16
GCST008363_24	Offspring birth weight	1.000000e-09
GCST90000025_791	Appendicular lean mass	4.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3706 (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: 213,432 (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
CHEMBL131	PREDNISOLONE	4	140,604
CHEMBL279785	MARIMASTAT	3	29,447
CHEMBL75094	PRINOMASTAT	3	8,839
CHEMBL115653	CIPEMASTAT	2	359
CHEMBL19611	ILOMASTAT	2	12,065
CHEMBL206815	APRATASTAT	2	256
CHEMBL279786	BATIMASTAT	2	21,247
CHEMBL440498	CTS-1027	2	615

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10929587	ADAM17		0.00	0
rs2276338	ADAM17, IAH1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
IK-862	Inhibition	9.25	pKi
BMS-561392	Inhibition	8.7	pIC50
ilomastat	Inhibition	8.12	pIC50
SL422	Inhibition	7.92	pKi
apratastat	Inhibition	7.7	pIC50
GI254023X	Inhibition	3.27	pIC50

Binding affinities (BindingDB)

793 measured of 1176 human assays (1221 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
BMCL181958 Compound 1	KI	0.06 nM
(1R,2S)-1-({3-fluoro-4-[(2-phenylquinolin-4-yl)methoxy]phenyl}methyl)-2-N-hydroxycyclopropane-1,2-dicarboxamide	KI	0.14 nM
(1S,2R)-1-N-hydroxy-2-({4-[(2-phenylquinolin-4-yl)methoxy]phenyl}methyl)cyclopropane-1,2-dicarboxamide	KI	0.18 nM
(1R,2S)-2-N-hydroxy-1-N,1-N-dimethyl-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}methyl)cyclopropane-1,2-dicarboxamide	KI	1 nM
2-{[4-(but-2-yn-1-ylamino)benzene]sulfonyl}ethane-1-thiol	KI	2 nM
5-[3-[4-(4-chloro-3,5-difluorophenyl)piperazin-1-yl]-2-methyl-3-oxopropyl]-5-(methoxymethyl)imidazolidine-2,4-dione	IC50	2 nM	US-9926281: 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis
(1S,2R)-1-N-hydroxy-2-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}methyl)cyclopropane-1,2-dicarboxamide	KI	3 nM
3-{[4-(but-2-yn-1-ylamino)benzene]sulfonyl}propane-1-thiol	KI	4.5 nM
(3S)-4-{[4-(but-2-yn-1-yloxy)benzene]sulfonyl}-N-hydroxy-2,2-dimethylthiomorpholine-3-carboxamide	IC50	4.7 nM
(1R,2R)-2-N-hydroxy-1-{3-[(2-methylquinolin-4-yl)methoxy]phenyl}-1-N-(propan-2-yl)cyclopropane-1,2-dicarboxamide	KI	5 nM
(3R)-1-{[4-(but-2-yn-1-ylamino)benzene]sulfonyl}pyrrolidine-3-thiol	KI	5 nM
(1S,3R)-6-{3-fluoro-4-[(2-phenylquinolin-4-yl)methoxy]phenyl}-N-hydroxy-4-oxo-5-azaspiro[2.4]heptane-1-carboxamide	KI	6.7 nM
propan-2-yl (1R,2R)-2-(hydroxycarbamoyl)-1-{3-[(2-methylquinolin-4-yl)methoxy]phenyl}cyclopropane-1-carboxylate	KI	8 nM
methyl (1R,2S)-2-(hydroxycarbamoyl)-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}methyl)cyclopropane-1-carboxylate	KI	8 nM
2-{[4-(but-2-yn-1-yloxy)benzene]sulfonyl}ethane-1-thiol	KI	8 nM
4-but-2-ynoxy-N-[(2S)-3-(hydroxyamino)-3-oxo-2-piperidin-1-ylpropyl]benzamide	IC50	9 nM	US-9266848: 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
(1R,2R)-1-N-cyclohexyl-2-N-hydroxy-1-{3-[(2-methylquinolin-4-yl)methoxy]phenyl}cyclopropane-1,2-dicarboxamide	KI	9 nM
methyl (1R,2R)-1-{3-[(3,4-dichlorophenyl)methoxy]phenyl}-2-(hydroxycarbamoyl)cyclopropane-1-carboxylate	KI	11 nM
(1R,2R)-2-N-hydroxy-1-{3-[(2-methylquinolin-4-yl)methoxy]phenyl}-1-N-phenylcyclopropane-1,2-dicarboxamide	KI	11 nM
1-{[4-(but-2-yn-1-ylamino)benzene]sulfonyl}azetidine-3-thiol	KI	11 nM
methyl (1R,2R)-2-(hydroxycarbamoyl)-1-{3-[(2-methylquinolin-4-yl)methoxy]phenyl}cyclopropane-1-carboxylate	KI	12 nM
1-{[4-(but-2-yn-1-yloxy)benzene]sulfonyl}azetidine-3-thiol	KI	13 nM
(1R,2S)-2-N-hydroxy-1-N-methyl-1-({4-[(2-methylquinolin-4-yl)methoxy]phenyl}methyl)cyclopropane-1,2-dicarboxamide	KI	14 nM
ethyl (1R,2R)-2-(hydroxycarbamoyl)-1-{3-[(2-methylquinolin-4-yl)methoxy]phenyl}cyclopropane-1-carboxylate	KI	16 nM
3-{[4-(but-2-yn-1-ylamino)benzene]sulfonyl}cyclohexane-1-thiol	KI	17 nM
methyl (1R,2R)-2-(hydroxycarbamoyl)-1-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)cyclopropane-1-carboxylate	KI	18 nM
(2S)-N-hydroxy-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]-2-(4-methylsulfonylpiperazin-1-yl)propanamide	IC50	21 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
4-[(4-fluorophenyl)methoxy]-N-[(2S)-3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]benzamide	IC50	21 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
4-but-2-ynoxy-N-[(2S)-3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]-N-methylbenzamide	IC50	22 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
(2S)-N-hydroxy-2-(4-methylsulfonylpiperazin-1-yl)-3-[[4-[(2-phenyl-4-pyridinyl)methoxy]phenyl]sulfonylamino]propanamide	IC50	24 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
5-[3-[4-(4-chloro-3-fluorophenyl)piperazin-1-yl]-3-oxopropyl]-5-phenylimidazolidine-2,4-dione	IC50	26 nM	US-9926281: 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis
2-{4-(but-2-yn-1-yloxy)benzenesulfonamido}-N-hydroxyacetamide	KI	27 nM
4-(but-2-yn-1-yloxy)-N-methyl-N-[(2S)-2-sulfanylpropyl]benzene-1-sulfonamide	KI	27 nM
(1S,3R)-N-hydroxy-4-oxo-6-{4-[(2-phenylquinolin-4-yl)methoxy]phenyl}-5-azaspiro[2.4]heptane-1-carboxamide	KI	30 nM
3-{[4-(but-2-yn-1-yloxy)benzene]sulfonyl}cyclohexane-1-thiol	KI	30 nM
(2S)-3-[(4-but-2-ynoxyphenyl)sulfonylamino]-N-hydroxy-2-(4-methylsulfonylpiperazin-1-yl)propanamide	IC50	32 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
4-but-2-ynoxy-N-[3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]benzamide	IC50	32 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
(1S,3R)-N-hydroxy-4-oxo-6-(4-{[2-(pyridin-3-yl)quinolin-4-yl]methoxy}phenyl)-5-azaspiro[2.4]heptane-1-carboxamide	KI	32 nM
(1S,3R)-N-hydroxy-6-{4-[(2-methylquinolin-4-yl)methoxy]phenyl}-4-oxo-5-azaspiro[2.4]heptane-1-carboxamide	KI	32 nM
(2S)-N-hydroxy-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]-2-(4-propan-2-ylsulfonylpiperazin-1-yl)propanamide	IC50	33 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(1S,3R)-N-hydroxy-4-oxo-6-(4-{[2-(pyridin-4-yl)quinolin-4-yl]methoxy}phenyl)-5-azaspiro[2.4]heptane-1-carboxamide	KI	33 nM
(3S)-1-{[4-(but-2-yn-1-yloxy)benzene]sulfonyl}pyrrolidine-3-thiol	KI	33 nM
N-[(2S)-3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]-4-(4-hydroxybut-2-ynoxy)benzamide	IC50	35 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
marimastat	IC50	35.8 nM
5-[3-(4-isoquinolin-6-ylpiperazin-1-yl)-3-oxopropyl]-5-phenylimidazolidine-2,4-dione	IC50	38 nM	US-9926281: 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis
5-[3-[4-(3,4-difluorophenyl)piperazin-1-yl]-2-methyl-3-oxopropyl]-5-(methoxymethyl)imidazolidine-2,4-dione	IC50	38 nM	US-9926281: 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis
N-[(2S)-3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]-4-phenylmethoxybenzamide	IC50	40 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
(1S,3R)-6-{3-fluoro-4-[(2-phenylquinolin-4-yl)methoxy]phenyl}-4-oxo-5-azaspiro[2.4]heptane-1-carboxylic acid	KI	40 nM
(2S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]propanamide	IC50	41 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
N-[(2S)-2-(4-ethylpiperazin-1-yl)-3-(hydroxyamino)-3-oxopropyl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide	IC50	45 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors

ChEMBL bioactivities

2398 potent at pChembl≥5 of 2500 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.59	IC50	0.026	nM	CHEMBL391851
10.22	Ki	0.06	nM	CHEMBL148169
10.22	Ki	0.06	nM	CHEMBL1288122
10.15	Ki	0.07	nM	CHEMBL1288000
10.00	IC50	0.1	nM	CHEMBL4082554
10.00	Ki	0.1	nM	CHEMBL1222942
10.00	Ki	0.1	nM	CHEMBL1288726
10.00	IC50	0.1	nM	CHEMBL1630098
9.89	Ki	0.13	nM	CHEMBL1288059
9.85	Ki	0.14	nM	CHEMBL461220
9.85	Ki	0.14	nM	CHEMBL495569
9.85	IC50	0.14	nM	CHEMBL271235
9.85	Ki	0.14	nM	CHEMBL1287998
9.82	Ki	0.15	nM	CHEMBL468778
9.82	Ki	0.15	nM	CHEMBL512117
9.80	Ki	0.16	nM	CHEMBL1287909
9.80	Ki	0.16	nM	CHEMBL1287939
9.77	Ki	0.17	nM	CHEMBL1288241
9.74	Ki	0.18	nM	CHEMBL461221
9.74	Ki	0.18	nM	CHEMBL1287969
9.72	Ki	0.19	nM	CHEMBL1288267
9.70	IC50	0.2	nM	CHEMBL432079
9.70	Ki	0.2	nM	CHEMBL4095412
9.70	Ki	0.2	nM	CHEMBL4085232
9.70	IC50	0.2	nM	CHEMBL489100
9.70	Ki	0.2	nM	CHEMBL1222941
9.70	Ki	0.2	nM	CHEMBL1288029
9.70	Ki	0.2	nM	CHEMBL1779610
9.68	IC50	0.21	nM	CHEMBL147956
9.68	Ki	0.21	nM	CHEMBL467747
9.66	Ki	0.22	nM	CHEMBL1287999
9.64	IC50	0.23	nM	CHEMBL439983
9.60	Ki	0.25	nM	CHEMBL500112
9.59	Ki	0.26	nM	CHEMBL1288028
9.57	IC50	0.27	nM	CHEMBL1630106
9.55	Ki	0.28	nM	CHEMBL524072
9.55	IC50	0.28	nM	CHEMBL1630091
9.54	Ki	0.29	nM	CHEMBL1287881
9.52	IC50	0.3	nM	CHEMBL279078
9.52	Ki	0.3	nM	CHEMBL4089108
9.52	Ki	0.3	nM	CHEMBL506057
9.52	IC50	0.3	nM	CHEMBL1630100
9.48	IC50	0.33	nM	CHEMBL357203
9.48	IC50	0.33	nM	CHEMBL148373
9.46	IC50	0.35	nM	CHEMBL148169
9.44	Ki	0.36	nM	CHEMBL496309
9.42	Ki	0.38	nM	CHEMBL443884
9.40	IC50	0.4	nM	CHEMBL144188
9.40	IC50	0.4	nM	BATIMASTAT
9.40	IC50	0.4	nM	CHEMBL4071465

PubChem BioAssay actives

2253 with measured affinity, of 3055 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
4-[(2-methylquinolin-4-yl)methoxy]-N-(5-methyl-2,4,6-trioxo-1,3-diazinan-5-yl)benzamide	347023: Inhibition of TACE	ic50	<0.0001	uM
(3S,4S)-N-hydroxy-4-[[4-[(2-methylquinolin-4-yl)methoxy]benzoyl]amino]-1-prop-2-ynylpyrrolidine-3-carboxamide	347023: Inhibition of TACE	ic50	0.0001	uM
3-[2-[(4R)-4-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-2,5-dioxoimidazolidin-4-yl]ethynyl]benzonitrile	538176: Inhibition of TACE	ki	0.0001	uM
cis-(1R,2S)-1-[[3-fluoro-4-[(2-phenylquinolin-4-yl)methoxy]phenyl]methyl]-2-N-hydroxycyclopropane-1,2-dicarboxamide	1798700: TACE Inhibition Assay from Article 10.1016/j.bmcl.2008.11.034: “Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors.”	ki	0.0001	uM
cis-(1R,2S)-1-[[3-fluoro-4-[(2-pyridin-3-ylquinolin-4-yl)methoxy]phenyl]methyl]-2-N-hydroxycyclopropane-1,2-dicarboxamide	348867: Inhibition of human recombinant TACE	ki	0.0001	uM
cis-(1R,2S)-1-[[3-fluoro-4-[[2-(1-methylpyrazol-3-yl)quinolin-4-yl]methoxy]phenyl]methyl]-2-N-hydroxycyclopropane-1,2-dicarboxamide	348867: Inhibition of human recombinant TACE	ki	0.0001	uM
cis-(1R,2S)-1-[[3-fluoro-4-[(2-pyrrolidin-1-ylquinolin-4-yl)methoxy]phenyl]methyl]-2-N-hydroxycyclopropane-1,2-dicarboxamide	348867: Inhibition of human recombinant TACE	ki	0.0001	uM
(5R)-5-[2-[4-[6-(4-ethylpiperazin-1-yl)-3-hydroxy-2-pyridinyl]-3-fluorophenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0001	uM
(5R)-5-[4-(5-chloro-6-oxo-1H-pyridin-3-yl)phenyl]-5-[(5-fluoro-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	501547: Inhibition of TACE assessed as inhibition of pro-TNFalpha peptide cleavage	ki	0.0001	uM
(5R)-5-[2-[4-(3-hydroxy-2-pyridinyl)phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0001	uM
(5R)-5-[2-(2-fluorophenyl)ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0001	uM
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-(2-phenylethynyl)imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0001	uM
(2R)-2-[(3R)-3-amino-3-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]-2-oxopyrrolidin-1-yl]-N-hydroxy-3-methylbutanamide	548722: Inhibition of human TACE by fluorescent spectroscopy	ic50	0.0001	uM
(1S,2S,3R,4R)-N-hydroxy-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]bicyclo[2.2.1]hept-5-ene-2-carboxamide	1469857: Inhibition of recombinant TACE catalytic domain (unknown origin) using pro-TNFalpha peptide Abz-LAQAVRSSSR-Dpa as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by FRET assay	ic50	0.0001	uM
(2R)-N-hydroxy-2-[(3S)-3-methyl-3-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]-2-oxopyrrolidin-1-yl]propanamide	1798700: TACE Inhibition Assay from Article 10.1016/j.bmcl.2008.11.034: “Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors.”	ki	0.0001	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-2-(2-methylpropyl)-3-(quinolin-8-ylmethylamino)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0002	uM
(5R)-5-[2-[6-[(Z)-C-(4-ethylpiperazin-1-yl)-N-hydroxycarbonimidoyl]-3-pyridinyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
(5R)-5-[2-(3-fluorophenyl)ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
cis-(1R,2S)-2-N-hydroxy-1-[[4-[(2-phenylquinolin-4-yl)methoxy]phenyl]methyl]cyclopropane-1,2-dicarboxamide	1798700: TACE Inhibition Assay from Article 10.1016/j.bmcl.2008.11.034: “Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors.”	ki	0.0002	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-3-[2-(2-methyl-1,3-benzothiazol-5-yl)ethoxy]-2-(2-methylpropyl)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0002	uM
cis-(1R,2S)-1-[[3-fluoro-4-[(2-morpholin-4-ylquinolin-4-yl)methoxy]phenyl]methyl]-2-N-hydroxycyclopropane-1,2-dicarboxamide	348867: Inhibition of human recombinant TACE	ki	0.0002	uM
(5R)-5-[(5-fluoro-3-oxo-1H-isoindol-2-yl)methyl]-5-[4-(6-oxo-1H-pyridin-3-yl)phenyl]imidazolidine-2,4-dione	501547: Inhibition of TACE assessed as inhibition of pro-TNFalpha peptide cleavage	ki	0.0002	uM
(5R)-5-[2-(1H-indol-5-yl)ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
(5R)-5-[2-[4-[(Z)-N-hydroxy-C-(4-methylpiperazin-1-yl)carbonimidoyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
(5R)-5-[2-(1H-indol-6-yl)ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
(5R)-5-[2-[4-[(Z)-C-(4-ethylpiperazin-1-yl)-N-hydroxycarbonimidoyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
(5R)-5-[2-[4-[(E)-hydroxyiminomethyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0002	uM
(2R,3R)-4-(1,3-dihydroisoindol-2-yl)-2,3-dihydroxy-4-oxo-N-[[5-[[2-(trifluoromethyl)benzimidazol-1-yl]methyl]thiophen-2-yl]methyl]butanamide	598178: Inhibition of TACE	ki	0.0002	uM
(5S)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-[4-(1H-pyrazol-4-yl)furo[3,2-c]pyridin-2-yl]imidazolidine-2,4-dione	1467605: Inhibition of catalytic domain TACE (unknown origin) by FRET assay	ki	0.0002	uM
(5S)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-(4-oxo-5H-furo[3,2-c]pyridin-2-yl)imidazolidine-2,4-dione	1467605: Inhibition of catalytic domain TACE (unknown origin) by FRET assay	ki	0.0002	uM
(2R)-2-[(3R)-3-amino-3-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]-2-oxopyrrolidin-1-yl]-N-hydroxy-4-methylpentanamide	347023: Inhibition of TACE	ic50	0.0002	uM
(2S,3R)-N-hydroxy-N’-[(2S)-1-(methylamino)-1-oxo-3-phenylpropan-2-yl]-3-(2-methylpropyl)-2-prop-2-enylbutanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0002	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-2-(2-methylpropyl)-3-(naphthalen-1-ylmethoxy)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0003	uM
(2R,3S)-3-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methoxy]-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-2-(2-methylpropyl)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0003	uM
N-hydroxy-4-(4-hydroxyphenyl)-2-[(6-methyl-2-oxochromen-3-yl)methyl]butanamide	548722: Inhibition of human TACE by fluorescent spectroscopy	ic50	0.0003	uM
4-[4-[2-(diethylamino)ethoxy]phenyl]-N-hydroxy-2-[(7-methyl-2-oxochromen-3-yl)methyl]butanamide	548722: Inhibition of human TACE by fluorescent spectroscopy	ic50	0.0003	uM
N-hydroxy-2-[(6-methyl-2-oxochromen-3-yl)methyl]-5-[3-(2-piperidin-1-ylethoxy)phenyl]pentanamide	548722: Inhibition of human TACE by fluorescent spectroscopy	ic50	0.0003	uM
(5R)-5-[2-(4-fluorophenyl)ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0003	uM
cis-(1R,2S)-2-N-hydroxy-1-N,1-N-dimethyl-1-[[4-[(2-phenylquinolin-4-yl)methoxy]phenyl]methyl]cyclopropane-1,2-dicarboxamide	348867: Inhibition of human recombinant TACE	ki	0.0003	uM
cis-(1S,2R)-N-hydroxy-2-[(2S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-2-[[4-[(2-phenylquinolin-4-yl)methoxy]phenyl]methyl]cyclopropane-1-carboxamide	348867: Inhibition of human recombinant TACE	ki	0.0003	uM
cis-(1S,2R)-N-hydroxy-2-[(3S)-3-hydroxypyrrolidine-1-carbonyl]-2-[[4-[(2-phenylquinolin-4-yl)methoxy]phenyl]methyl]cyclopropane-1-carboxamide	348867: Inhibition of human recombinant TACE	ki	0.0003	uM
(5R)-5-[2-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]ethynyl]-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	538176: Inhibition of TACE	ki	0.0003	uM
(5S)-5-(1-benzofuran-2-yl)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	1467605: Inhibition of catalytic domain TACE (unknown origin) by FRET assay	ki	0.0003	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-3-[(1-methyl-2-oxoquinolin-3-yl)methoxy]-2-(2-methylpropyl)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0004	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-2-(2-methylpropyl)-3-(quinolin-8-ylmethoxy)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0004	uM
(2S,3S)-3-(3,5-dichlorophenyl)sulfanyl-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-2-(2-methylpropyl)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0004	uM
cis-(1R,2R)-N,1-dihydroxy-2-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]cyclopentane-1-carboxamide	1443192: Inhibition of recombinant TACE catalytic domain (unknown origin) using Abz-LAQAVRSSSR-Dpa as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by FRET assay	ic50	0.0004	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’,3-dihydroxy-2-(2-methylpropyl)butanediamide	210018: Inhibition of recombinant human TNF-alpha converting enzyme (TACE)	ki	0.0004	uM
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N’-hydroxy-3-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methoxy]-2-(2-methylpropyl)butanediamide	215431: Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.	ic50	0.0004	uM
(5S)-5-(7-aminofuro[3,2-c]pyridin-2-yl)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]imidazolidine-2,4-dione	1467605: Inhibition of catalytic domain TACE (unknown origin) by FRET assay	ki	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, increases reaction, decreases expression, affects cotreatment	4
sodium arsenite	decreases expression, increases expression	3
Tetradecanoylphorbol Acetate	decreases reaction, affects localization, decreases cleavage, increases cleavage, increases reaction (+3 more)	3
Cyclosporine	increases expression	3
U 0126	affects expression, affects reaction, increases expression	2
Acrolein	affects cotreatment, increases oxidation, increases expression, increases reaction, increases abundance	2
Tretinoin	affects localization, increases expression	2
Valproic Acid	decreases expression, increases expression	2
Copper Sulfate	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
4-methylumbelliferone 8-carbaldehyde	decreases reaction, increases expression	1
dicrotophos	decreases expression	1
thymoquinone	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
withaferin A	decreases reaction, increases cleavage, increases reaction, increases activity, increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
N(6),N(6)-dimethyladenosine	decreases reaction, decreases stability, decreases expression	1
hydroquinone	affects reaction, increases secretion, decreases reaction, increases expression, increases stability	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
cordycepin	decreases expression, decreases reaction, decreases stability	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, decreases reaction	1
4-phenylbutyric acid	decreases reaction, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases reaction, increases expression, increases stability	1
4-hydroxyisoleucine	decreases expression	1

ChEMBL screening assays

288 unique, capped per target: 257 binding, 25 functional, 5 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001173	Binding	Inhibition of human recombinant TACE	Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3’ pocket. — Bioorg Med Chem Lett
CHEMBL1640793	Functional	Inhibition of human TNF-alpha by fluorescent spectroscopy	Structure based optimization of chromen-based TNF-α converting enzyme (TACE) inhibitors on S1’ pocket and their quantitative structure-activity relationship (QSAR) study. — Bioorg Med Chem
CHEMBL3868407	ADMET	Inhibition of recombinant human TACE using Cy3-PLAQAV(Cy5Q-L-2,3-diaminopropionic acid)-RSSSR-NH2 as substrate measured after 40 mins by spectrofluorimetric method	Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0ZA	Abcam K-562 ADAM17 KO	Cancer cell line	Female
CVCL_B1D7	Abcam HCT 116 ADAM17 KO	Cancer cell line	Male
CVCL_B1IZ	Abcam HeLa ADAM17 KO	Cancer cell line	Female
CVCL_D7JK	Ubigene A-549 ADAM17 KO	Cancer cell line	Male
CVCL_D8H4	Ubigene HCT 116 ADAM17 KO	Cancer cell line	Male
CVCL_D8YP	Ubigene HEK293 ADAM17 KO	Transformed cell line	Female
CVCL_D9X6	Ubigene HeLa ADAM17 KO	Cancer cell line	Female
CVCL_KT29	HeLa SilenciX ADAM17	Cancer cell line	Female
CVCL_SB47	HAP1 ADAM17 (-) 1	Cancer cell line	Male
CVCL_SB48	HAP1 ADAM17 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE