ADAM10

Summary

ADAM10 (ADAM metallopeptidase domain 10, HGNC:188) is a protein-coding gene on chromosome 15q21.3, encoding Disintegrin and metalloproteinase domain-containing protein 10 (O14672). Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins, including adhesion proteins, growth factor precursors and cytokines being essential for development and tissue homeostasis.

Members of the ADAM family are cell surface proteins with a unique structure possessing both potential adhesion and protease domains. This gene encodes and ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin. Alternate splicing results in multiple transcript variants encoding different proteins that may undergo similar processing.

Source: NCBI Gene 102 — RefSeq curated summary.

At a glance

• Gene–disease (curated): reticulate acropigmentation of Kitamura (Strong, GenCC)
• GWAS associations: 13
• Clinical variants (ClinVar): 137 total — 12 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 5
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:188
Approved symbol	ADAM10
Name	ADAM metallopeptidase domain 10
Location	15q21.3
Locus type	gene with protein product
Status	Approved
Aliases	kuz, MADM, HsT18717, CD156C
Ensembl gene	ENSG00000137845
Ensembl biotype	protein_coding
OMIM	602192
Entrez	102

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 5 protein_coding_CDS_not_defined, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000260408, ENST00000396136, ENST00000402627, ENST00000439637, ENST00000461408, ENST00000462061, ENST00000470269, ENST00000475898, ENST00000481164, ENST00000482945, ENST00000497846, ENST00000558004, ENST00000558733, ENST00000559053, ENST00000560608, ENST00000561149, ENST00000561288, ENST00000861945, ENST00000933846, ENST00000933847, ENST00000933848, ENST00000944911, ENST00000944912, ENST00000944913, ENST00000944914

RefSeq mRNA: 2 — MANE Select: NM_001110 NM_001110, NM_001320570

CCDS: CCDS10167

Canonical transcript exons

ENST00000260408 — 16 exons

Exon	Start	End
ENSE00001809760	58588809	58597641
ENSE00002542201	58749480	58749707
ENSE00003462446	58643886	58643978
ENSE00003477324	58633196	58633359
ENSE00003490982	58621471	58621621
ENSE00003503014	58599598	58599724
ENSE00003559202	58679124	58679282
ENSE00003581776	58640777	58640960
ENSE00003582465	58646055	58646204
ENSE00003591868	58627700	58627883
ENSE00003615258	58717577	58717727
ENSE00003632357	58682196	58682314
ENSE00003637170	58610999	58611107
ENSE00003638942	58610297	58610517
ENSE00003661775	58665097	58665197
ENSE00003681481	58611808	58611991

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.6480 / max 371.7705, expressed in 1816 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150239	33.5507	1815
150240	5.5399	1539
207542	0.3640	180
150242	0.1181	31
150241	0.0753	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.42	gold quality
amniotic fluid	UBERON:0000173	98.38	gold quality
trigeminal ganglion	UBERON:0001675	98.04	gold quality
visceral pleura	UBERON:0002401	98.04	gold quality
monocyte	CL:0000576	97.96	gold quality
mononuclear cell	CL:0000842	97.95	gold quality
oocyte	CL:0000023	97.79	gold quality
olfactory bulb	UBERON:0002264	97.78	gold quality
placenta	UBERON:0001987	97.72	gold quality
leukocyte	CL:0000738	97.65	gold quality
colonic epithelium	UBERON:0000397	97.45	gold quality
bone marrow cell	CL:0002092	97.41	gold quality
corpus callosum	UBERON:0002336	97.38	gold quality
pleura	UBERON:0000977	97.36	gold quality
choroid plexus epithelium	UBERON:0003911	97.36	gold quality
ventricular zone	UBERON:0003053	97.32	gold quality
lower lobe of lung	UBERON:0008949	97.28	gold quality
inferior vagus X ganglion	UBERON:0005363	97.25	gold quality
germinal epithelium of ovary	UBERON:0001304	97.20	gold quality
buccal mucosa cell	CL:0002336	97.14	gold quality
mammary duct	UBERON:0001765	97.10	gold quality
endometrium	UBERON:0001295	97.04	gold quality
epithelium of mammary gland	UBERON:0003244	97.04	gold quality
parietal pleura	UBERON:0002400	97.01	gold quality
globus pallidus	UBERON:0001875	96.98	gold quality
medial globus pallidus	UBERON:0002477	96.93	gold quality
subthalamic nucleus	UBERON:0001906	96.89	gold quality
sural nerve	UBERON:0015488	96.89	gold quality
periodontal ligament	UBERON:0008266	96.87	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.84	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	6420.87
E-HCAD-31	yes	4054.75
E-ANND-3	yes	11.20

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ERBB4	Repression

Upstream regulators (CollecTRI, top): AP1, HDAC1, PAX2, RARB, SOX2, SP1, TBX2, USF1

miRNA regulators (miRDB)

288 targeting ADAM10, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883

Literature-anchored findings (GeneRIF, showing 40)

• Atrial fibrillation is associated with an increase in the expression of ADAM10 in the heart atrium (PMID:11839628)
• [alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients. (PMID:12080182)
• ADAM10 mRNA levels were twofold higher in the hippocampus and cerebellum of Alzheimer’s disease patients compared to controls, but without relationship to the severity of anatomical damage. (PMID:12438920)
• 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 mode of activation of EGFR in response to bacterial lipoteichoic acid involves cleavage of the transmembrane ligand HBEGF by ADAM 10. (PMID:12568494)
• Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/gamma-secretase activity in the functional regulation of adhesion molecules. (PMID:12629514)
• gamma-secretase cleavage of CT99 is a prerequisite for BACE-mediated processing at Abeta-34 site and therefore, BACE and gamma-secretase activity can be mutually dependent. (PMID:12665519)
• 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)
• variation at the ADAM10 gene locus is not associated with Creutzfeldt-Jakob disease (PMID:12782344)
• gamma secretase is regulated by nicastrin (PMID:12815056)
• cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (PMID:12832423)
• gamma-secretase is engaged directly by Notch activation, which leads to diminished PS1 expression, suggesting a complex set of feedback interactions following Notch activation (PMID:12960155)
• APH-1 plays a GXXXG-dependent scaffolding role in both the initial assembly and subsequent maturation and maintenance of the active gamma-secretase complex. (PMID:14627705)
• Purified cholesterol-rich microdomains from a low-density membrane fraction demonstrate gamma-secretase/ADAM10 activity, indicating that amyloid beta protein production can take place in rafts. (PMID:14636066)
• ADAM 10, a putative alpha-secretase involved in Notch signaling, was found in neurons of the perinatal cortex. During aging there is an increase in intraneuronal staining intensity and in the number of cortical nerve cells that contain the enzyme (PMID:14707550)
• 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)
• NRADD is an additional gamma-secretase substrate (PMID:15280425)
• IL-8 induces shedding of EGFR ligands because of an ADAM10-dependent pathway in gastric cancer cells (PMID:15300588)
• ADAM10 mediates constitutive and activated pro-BTC shedding (PMID:15507448)
• Expression of a dominant-negative form of kuzbanian in transgenic mice leads to reduced T-cell receptor beta expression in double-negative thymocytes and to a partial block between the double-negative to double-positive stages of development. (PMID:15905513)
• ADAM10 has a role in E-cadherin shedding and epithelial cell-cell adhesion, migration, and beta-catenin translocation (PMID:15958533)
• Data suggest a simple mechanism for regulating ADAM10-mediated ephrin proteolysis, which ensures that only Eph bound ephrins are recognized and cleaved. (PMID:16239146)
• High levels of Prpc C-terminal fragment (C1) are associated with the presence of the active ADAM 10 suggesting this zinc metalloprotease as a candidate for the cleavage of PrP(c) in the human brain. (PMID:16263114)
• Result suggests that ADAM10 expression plays a role in the carcinogenesis of oral squamous cell carcinoma (OSCC) and proliferation of OSCC cells, independent of APP processing. (PMID:16309826)
• EGF induces ADAM10-mediated CD44 cleavage through Rac1 and mitogen-activated protein kinase activation, and thereby promotes tumour cell migration and invasion. (PMID:16390331)
• ADAM10 is a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating a variety of breast cancers with active HER2 signaling. (PMID:16627989)
• ADAM10 mediates cleavage of a receptor tyrosine phosphatase and regulation of beta catenin’s transcriptional activity. (PMID:16648485)
• ADAM10-mediated release of CD46 from apoptotic vesicles may represent a form of strategy to allow restricted complement activation to deal with modified self (PMID:16735514)
• ADAM10 is the protease responsible for constitutive and regulated Pcdh gamma shedding events that modulate the cell adhesion role of Pcdh gamma. (PMID:16751190)
• ADAM9 does not behave as a genuine alpha-secretase but rather acts as an important upstream regulator of ADAM10 activity. (PMID:16806063)
• furin enhances alpha-secretase activity via the cleavage of ADAM10 and TACE, and attenuated furin activity is connected to the production of Abeta (PMID:16942750)
• ADAM-10 transgenic mice display significantly elevated cortical cholinergic, glutaminergic and GABAergic presynaptic bouton densities at an early developmental time point. (PMID:17187903)
• These findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death. (PMID:17290285)
• ADAM10 and SPPL2a were identified as two proteases implicated in FasL processing and release of the FasL intracellular domain, which has been shown to be important for retrograde FasL signaling (PMID:17557115)
• ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. (PMID:17699774)
• In human prostate cancer, the nuclear translocation of ADAM-10 coupled with the androgen receptor is involved in tumor growth and progression. (PMID:17727679)
• the ADAM10 prodomain inhibits betacellulin shedding, demonstrating that it could be of potential use as a therapeutic agent to treat cancer. (PMID:17895248)
• SPPL2a and SPPL2b mediate the intramembrane cleavage, whereas neither SPP nor SPPL3 is capable of processing the Bri2 N-terminal fragment. (PMID:17965014)
• ADAM10 is identified as the TSHR cleavage enzyme and it is shown that TSH regulates its activation. (PMID:18074395)
• ADAM10-mediated E-cadherin proteolysis leads to the impaired cohesion of keratinocytes observed in eczematous dermatitis. (PMID:18200054)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam10b	ENSDARG00000015502
danio_rerio	adam10a	ENSDARG00000053468
danio_rerio	adam9b	ENSDARG00000057138
mus_musculus	Adam10	ENSMUSG00000054693
rattus_norvegicus	Adam10	ENSRNOG00000054257
drosophila_melanogaster	mmd	FBGN0259110
drosophila_melanogaster	kuz	FBGN0259984
caenorhabditis_elegans	sup-17	WBGENE00006324
caenorhabditis_elegans		WBGENE00006804

Paralogs (20): ADAM22 (ENSG00000008277), ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM21 (ENSG00000139985), ADAM15 (ENSG00000143537), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 10 — O14672 (reviewed: O14672)

Alternative names: CDw156, Kuzbanian protein homolog, Mammalian disintegrin-metalloprotease

All UniProt accessions (8): A0A087WYG1, B5MC71, C9J9B4, O14672, H0YK32, H0YK87, H0YNC5, H3BS53

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 being essential for development and tissue homeostasis. Associates with six members of the tetraspanin superfamily TspanC8 which regulate its exit from the endoplasmic reticulum and its substrate selectivity. Cleaves the membrane-bound precursor of TNF at ‘76-Ala-|-Val-77’ 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 heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP). Contributes to the normal cleavage of the cellular prion protein. Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity. Also controls the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis. Required for the development of type 1 transitional B cells into marginal zone B cells, probably by cleaving Notch. Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form. Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B. Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3. Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA. Enhances the cleavage of CHL1 by BACE1. Cleaves NRCAM. Cleaves TREM2, resulting in shedding of the TREM2 ectodomain. Involved in the development and maturation of glomerular and coronary vasculature. During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions. May regulate the EFNA5-EPHA3 signaling. Regulates leukocyte transmigration as a sheddase for the adherens junction protein VE-cadherin/CDH5 in endothelial cells. (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.

Subunit / interactions. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Interacts with the clathrin adapter AP2 complex subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons. Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions. Interacts with EPHA2. Interacts with NGF in a divalent cation-dependent manner. Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression. Interacts with TSPAN5, TSPAN10, TSPAN14, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity, endocytosis and turnover. Interacts (via extracellular domain) with TSPAN33 (via extracellular domain) and (via cytoplasmic domain) with AFDN; interaction with TSPAN33 allows the docking of ADAM10 to zonula adherens through a PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while interaction with AFDN locks ADAM10 at zonula adherens. Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons. Interacts (via extracellular domain) with BACE1 (via extracellular domain). Interacts with FAM171A1. (Microbial infection) Interacts with S.aureus hly; this interaction is necessary for toxin pore formation, disruption of focal adhesions and S.aureus hly-mediated cytotoxicity.

Subcellular location. Cell membrane. Golgi apparatus membrane. Cytoplasmic vesicle. Clathrin-coated vesicle. Cell projection. Axon. Dendrite. Cell junction. Adherens junction. Cytoplasm.

Tissue specificity. Expressed in the brain (at protein level). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver.

Post-translational modifications. The precursor is cleaved by furin and PCSK7.

Disease relevance. Reticulate acropigmentation of Kitamura (RAK) [MIM:615537] A rare cutaneous pigmentation disorder characterized by reticulate, slightly depressed, sharply demarcated brown macules without hypopigmentation, affecting the dorsa of the hands and feet and appearing in the first or second decade of life. The macules gradually darken and extend to the proximal regions of the extremities. The manifestations tend to progress until middle age, after which progression of the eruptions stops. The pigmentary augmentation is found on the flexor aspects of the wrists, neck, patella and olecranon. Other features include breaks in the epidermal ridges on the palms and fingers, palmoplantar pits, occasionally plantar keratoderma, and partial alopecia. The disease is caused by variants affecting the gene represented in this entry. Alzheimer disease 18 (AD18) [MIM:615590] A late-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Catalytically inactive when the propeptide is intact and associated with the mature enzyme. The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme. The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins. Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33. Stalk region is sufficient for interaction with TSPAN15.

Induction. In osteoarthritis affected-cartilage.

Isoforms (2)

UniProt ID	Names	Canonical?
O14672-1	1	yes
O14672-2	2

RefSeq proteins (2): NP_001101, NP_001307499 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001590	Peptidase_M12B	Domain
IPR001762	Disintegrin_dom	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034025	ADAM10_ADAM17	Domain
IPR036436	Disintegrin_dom_sf	Homologous_superfamily
IPR049038	ADAM10_Cys-rich	Domain
IPR051489	ADAM_Metalloproteinase	Family

Pfam: PF00200, PF13574, PF21299

Enzyme classification (BRENDA):

• EC 3.4.24.81 — ADAM10 endopeptidase (BRENDA: 8 organisms, 153 substrates, 85 inhibitors, 2 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLU(EDANS)-PRO-LEU-ALA-GLN-ALA-VAL-ARG-SER-SER(G	0.0085	1
GLU(EDANS)-PRO-LEU-ALA-GLN-ALA-VAL-ARG-SER-SER-S	0.012	1

UniProt features (99 total): strand 21, helix 18, disulfide bond 17, turn 6, sequence variant 5, binding site 4, glycosylation site 4, mutagenesis site 4, short sequence motif 3, sequence conflict 3, topological domain 2, domain 2, region of interest 2, signal peptide 1, propeptide 1, active site 1, site 1, modified residue 1, chain 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6BE6	X-RAY DIFFRACTION	2.8
6BDZ	X-RAY DIFFRACTION	3.1
8ESV	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14672-F1	80.17	0.38

Antibody-complex structures (SAbDab): 2 — 6BDZ, 8ESV

Functional residue map

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

Catalytic / active sites (2): 384; 213–214 (cleavage; by furin and pcsk7)

Ligand- & substrate-binding residues (4): 173 (in inhibited form); 383; 387; 393

Post-translational modifications (1): 719

Disulfide bonds (17): 222–313, 344–451, 399–435, 460–495, 471–484, 473–479, 483–515, 503–511, 510–536, 524–543, 530–562, 555–567, 572–598, 580–607, 582–597, 594–639, 632–645

Glycosylation sites (4): 267, 278, 439, 551

Mutagenesis-validated functional residues (4):

Position	Phenotype
384	loss of proteolytic activity. abrogates app cleavage. reduces notch signaling.
638–646	strongly reduces interaction and adam10 maturation.
638–646	strongly reduces interaction and prevents adam10 maturation.
653–656	strongly reduces interaction and prevents adam10 maturation.

Function

Pathways and Gene Ontology

Reactome pathways

39 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-177929	Signaling by EGFR
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-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-6798695	Neutrophil degranulation
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-977225	Amyloid fiber formation
R-HSA-1266738	Developmental Biology
R-HSA-1474244	Extracellular matrix organization
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
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-2682334	EPH-Ephrin signaling
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer

MSigDB gene sets: 504 (showing top): REACTOME_SIGNALING_BY_NOTCH, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_MSN, GOBP_REGULATION_OF_T_CELL_CHEMOTAXIS, GOBP_CELL_CHEMOTAXIS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_MIGRATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH

GO Biological Process (32): in utero embryonic development (GO:0001701), membrane protein ectodomain proteolysis (GO:0006509), negative regulation of cell adhesion (GO:0007162), epidermal growth factor receptor signaling pathway (GO:0007173), Notch signaling pathway (GO:0007219), integrin-mediated signaling pathway (GO:0007229), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), regulation of Notch signaling pathway (GO:0008593), negative regulation of gene expression (GO:0010629), positive regulation of T cell chemotaxis (GO:0010820), protein processing (GO:0016485), extracellular matrix disassembly (GO:0022617), positive regulation of cell growth (GO:0030307), positive regulation of cell migration (GO:0030335), positive regulation of tumor necrosis factor production (GO:0032760), adherens junction organization (GO:0034332), response to tumor necrosis factor (GO:0034612), epidermal growth factor receptor ligand maturation (GO:0038004), monocyte activation (GO:0042117), amyloid precursor protein catabolic process (GO:0042987), pore complex assembly (GO:0046931), constitutive protein ectodomain proteolysis (GO:0051089), cochlea development (GO:0090102), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), postsynapse organization (GO:0099173), regulation of postsynapse organization (GO:0099175), protein catabolic process at postsynapse (GO:0140249), regulation of vasculature development (GO:1901342), positive regulation of tumor necrosis factor-mediated signaling pathway (GO:1903265), proteolysis (GO:0006508), signaling receptor ligand precursor processing (GO:0140448)

GO Molecular Function (12): endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), integrin binding (GO:0005178), metallopeptidase activity (GO:0008237), SH3 domain binding (GO:0017124), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), metallodipeptidase activity (GO:0070573), metalloendopeptidase activity involved in amyloid precursor protein catabolic process (GO:1902945), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (25): Golgi membrane (GO:0000139), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), Golgi-associated vesicle (GO:0005798), plasma membrane (GO:0005886), adherens junction (GO:0005912), focal adhesion (GO:0005925), cell surface (GO:0009986), postsynaptic density (GO:0014069), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), axon (GO:0030424), dendrite (GO:0030425), specific granule membrane (GO:0035579), pore complex (GO:0046930), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), perinuclear endoplasmic reticulum (GO:0097038), synaptic membrane (GO:0097060), tetraspanin-enriched microdomain (GO:0097197), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Metabolism of proteins	2
Degradation of the extracellular matrix	1
Extracellular matrix organization	1
Signaling by Receptor Tyrosine Kinases	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
Signaling by NOTCH2	1
EPH-Ephrin signaling	1
Innate Immune System	1
Post-translational protein modification	1
Signaling by NOTCH3	1
Signaling by NOTCH4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell surface receptor signaling pathway	2
positive regulation of cellular process	2
peptidase activity	2
endoplasmic reticulum	2
neuron projection	2
secretory granule membrane	2
chordate embryonic development	1
membrane protein proteolysis	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
ERBB signaling pathway	1
cell communication	1
signaling	1
cell population proliferation	1
regulation of cell population proliferation	1
Notch signaling pathway	1
regulation of signal transduction	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
T cell chemotaxis	1
regulation of T cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
positive regulation of T cell migration	1
proteolysis	1
protein maturation	1
cellular component disassembly	1
extracellular matrix organization	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
cell-cell junction organization	1

Protein interactions and networks

STRING

3261 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM10	DLG1	Q12959	968
ADAM10	TSPAN33	Q86UF1	907
ADAM10	TSPAN14	Q8NG11	906
ADAM10	BACE1	P56817	890
ADAM10	APP	P05067	879
ADAM10	TSPAN5	P62079	871
ADAM10	PSEN1	P49768	847
ADAM10	EFNA2	O43921	825
ADAM10	CX3CL1	P78423	823
ADAM10	NCSTN	Q92542	807
ADAM10	TSPAN15	O95858	802
ADAM10	PSEN2	P49810	790
ADAM10	APH1A	Q96BI3	790
ADAM10	CXCL16	Q9H2A7	763
ADAM10	TSPAN18	Q96SJ8	761

IntAct

232 interactions, top by confidence:

A	B	Type	Score
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
ADAM10	TSPAN15	psi-mi:“MI:0915”(physical association)	0.840
TSPAN15	ADAM10	psi-mi:“MI:0915”(physical association)	0.840
ADAM10	TSPAN15	psi-mi:“MI:0403”(colocalization)	0.840
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
ADAM10	TSPAN5	psi-mi:“MI:0915”(physical association)	0.800
TSPAN5	ADAM10	psi-mi:“MI:0915”(physical association)	0.800
ADAM10	TSPAN5	psi-mi:“MI:0403”(colocalization)	0.800
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
ADAM10	CD9	psi-mi:“MI:0914”(association)	0.750
CD9	ADAM10	psi-mi:“MI:0915”(physical association)	0.750
CD9	ADAM10	psi-mi:“MI:0403”(colocalization)	0.750

BioGRID (110): DLG1 (Affinity Capture-Western), ADAM10 (Affinity Capture-Western), TSPAN5 (Affinity Capture-Western), ADAM10 (Affinity Capture-Western), ADAM10 (Affinity Capture-Western), ADAM10 (Affinity Capture-Western), ADAM10 (Affinity Capture-Western), ADAM10 (Affinity Capture-Western), ADAM10 (Affinity Capture-MS), ADAM10 (Affinity Capture-MS), ADAM10 (Synthetic Growth Defect), ADAM10 (Affinity Capture-MS), ADAM10 (Affinity Capture-RNA), ADAM10 (Co-localization), ADAM10 (Affinity Capture-MS)

ESM2 similar proteins: A0JPQ9, O14657, O14672, O19015, O35598, P09958, P16098, P23188, P23377, P58780, P82993, Q01458, Q01460, Q08169, Q0JJD4, Q10741, Q10743, Q10RB4, Q1L8D2, Q28193, Q29LW1, Q29NU5, Q4V8H8, Q58D55, Q5EAB4, Q5GF25, Q5RFF6, Q66IL0, Q68EX9, Q6NXH2, Q6ZJJ0, Q7SYK0, Q7Z1Z1, Q8BH64, Q8MLZ7, Q8MX31, Q8MX32, Q8MX40, Q8T0R7, Q922Q9

Diamond homologs: C5FUK3, C5H5D1, C5H5D3, C5H5D5, C5H5D6, D4B1G0, D4DCV9, O14672, O35598, O42596, O73795, O75077, O75078, O77633, O88839, O93517, O93518, O93523, P0C6E3, P0C6R9, P0DJ87, P0DM87, P17497, P83912, Q076D1, Q0NZX7, Q0NZX9, Q0NZY0, Q10741, Q10743, Q13443, Q13444, Q2LD49, Q4JCS0, Q4WQ08, Q60472, Q698K8, Q8AWI5, Q8AWX7, Q8JIY1

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
SP1	“up-regulates quantity by expression”	ADAM10	“transcriptional regulation”
ADAM10	“up-regulates activity”	NOTCH	cleavage
USF1	“up-regulates quantity by expression”	ADAM10	“transcriptional regulation”
ADAM10	“up-regulates activity”	NOTCH1	cleavage
ADAM10	“up-regulates activity”	BTC	cleavage
ADAM10	“up-regulates activity”	EGF	cleavage
ADAM10	“up-regulates activity”	ERBB2	cleavage
ADAM10	“up-regulates activity”	CDH1	cleavage
ADAM10	“up-regulates activity”	CD44	cleavage
ELAVL1	“up-regulates quantity”	ADAM10	“post transcriptional regulation”
ELAVL2	“up-regulates quantity”	ADAM10	“post transcriptional regulation”
ELAVL3	“up-regulates quantity”	ADAM10	“post transcriptional regulation”
ELAVL4	“up-regulates quantity”	ADAM10	“post transcriptional regulation”
TSPAN33	“up-regulates activity”	ADAM10	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 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
Regulation of KIT signaling	5	30.4×	7e-05
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	26.2×	1e-04
Regulation of signaling by CBL	5	25.1×	1e-04
Signaling by CSF1 (M-CSF) in myeloid cells	6	21.0×	7e-05
Co-stimulation by CD28	5	19.2×	2e-04
EPHA-mediated growth cone collapse	5	19.2×	2e-04
DAP12 signaling	5	18.6×	3e-04
Signaling by SCF-KIT	7	17.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
plasma membrane tubulation	6	50.3×	1e-06
negative regulation of natural killer cell mediated cytotoxicity	6	39.7×	2e-06
negative regulation of endocytosis	5	34.9×	5e-05
Fc-gamma receptor signaling pathway involved in phagocytosis	5	26.2×	2e-04
leukocyte migration	5	23.3×	3e-04
negative regulation of inflammatory response to antigenic stimulus	5	22.5×	3e-04
ephrin receptor signaling pathway	8	20.5×	2e-06
cellular response to amyloid-beta	5	14.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	1
Uncertain significance	71
Likely benign	5
Benign	31

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1807706	GRCh37/hg19 15q21.1-22.2(chr15:48589845-63543438)x3	Pathogenic
2685517	GRCh37/hg19 15q21.3-22.2(chr15:54020810-62086530)x1	Pathogenic
3391925	GRCh37/hg19 15q21.3-22.31(chr15:57544843-64324372)x1	Pathogenic
395193	GRCh37/hg19 15q21.3-22.2(chr15:54713558-62769295)x1	Pathogenic
442636	GRCh37/hg19 15q21.3-22.2(chr15:58088503-62221756)x1	Pathogenic
57220	GRCh38/hg38 15q21.3-22.2(chr15:57456076-61907285)x1	Pathogenic
57881	GRCh38/hg38 15q21.2-22.2(chr15:50864913-59646577)x1	Pathogenic
685183	GRCh37/hg19 15q21.1-22.2(chr15:48000433-60747551)x3	Pathogenic
88840	NM_001110.4(ADAM10):c.1511G>A (p.Ser504Asn)	Pathogenic
88841	NM_001110.4(ADAM10):c.429T>A (p.Tyr143Ter)	Pathogenic
88842	NM_001110.4(ADAM10):c.1264del (p.Thr422fs)	Pathogenic
88843	NM_001110.4(ADAM10):c.1571G>A (p.Cys524Tyr)	Pathogenic
442376	GRCh37/hg19 15q21.3(chr15:57518653-58974175)x3	Likely pathogenic

SpliceAI

3753 predictions. Top by Δscore:

Variant	Effect	Δscore
15:58610518:C:CC	acceptor_gain	1.0000
15:58610997:A:AC	donor_gain	1.0000
15:58610998:C:CC	donor_gain	1.0000
15:58610998:CTTTT:C	donor_gain	1.0000
15:58611103:CATTG:C	acceptor_gain	1.0000
15:58611806:ACC:A	donor_gain	1.0000
15:58611807:CCC:C	donor_gain	1.0000
15:58611992:C:CC	acceptor_gain	1.0000
15:58621466:GGTA:G	donor_loss	1.0000
15:58621467:GTACC:G	donor_loss	1.0000
15:58621468:TA:T	donor_loss	1.0000
15:58621469:ACCT:A	donor_loss	1.0000
15:58621470:C:CA	donor_loss	1.0000
15:58621470:CCT:C	donor_gain	1.0000
15:58621472:TGC:T	donor_gain	1.0000
15:58621473:G:A	donor_gain	1.0000
15:58621506:T:TA	donor_gain	1.0000
15:58621507:C:A	donor_gain	1.0000
15:58621617:AGATT:A	acceptor_gain	1.0000
15:58621618:GATT:G	acceptor_gain	1.0000
15:58621619:ATT:A	acceptor_gain	1.0000
15:58621619:ATTCT:A	acceptor_loss	1.0000
15:58621620:TT:T	acceptor_gain	1.0000
15:58621620:TTCTG:T	acceptor_loss	1.0000
15:58621621:TC:T	acceptor_loss	1.0000
15:58621622:C:CA	acceptor_loss	1.0000
15:58621622:C:CC	acceptor_gain	1.0000
15:58621631:A:AC	acceptor_gain	1.0000
15:58621631:A:C	acceptor_gain	1.0000
15:58627879:TCATG:T	acceptor_gain	1.0000

AlphaMissense

4980 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:58599654:C:T	C699Y	1.000
15:58599655:A:G	C699R	1.000
15:58599675:A:C	M692R	1.000
15:58599675:A:T	M692K	1.000
15:58599697:C:G	G685R	1.000
15:58599697:C:T	G685R	1.000
15:58610352:A:G	L657P	1.000
15:58610352:A:T	L657H	1.000
15:58610361:A:T	L654Q	1.000
15:58610368:C:A	G652C	1.000
15:58610387:G:C	C645W	1.000
15:58610388:C:A	C645F	1.000
15:58610388:C:G	C645S	1.000
15:58610388:C:T	C645Y	1.000
15:58610389:A:G	C645R	1.000
15:58610389:A:T	C645S	1.000
15:58610403:T:A	D640V	1.000
15:58610404:C:G	D640H	1.000
15:58610405:A:C	C639W	1.000
15:58610406:C:A	C639F	1.000
15:58610406:C:G	C639S	1.000
15:58610406:C:T	C639Y	1.000
15:58610407:A:G	C639R	1.000
15:58610407:A:T	C639S	1.000
15:58610409:T:C	Y638C	1.000
15:58610412:C:T	G637D	1.000
15:58610413:C:A	G637C	1.000
15:58610413:C:G	G637R	1.000
15:58610426:G:C	C632W	1.000
15:58610427:C:A	C632F	1.000

dbSNP variants (sampled 300 via entrez): RS1000017646 (15:58744828 A>G), RS1000032820 (15:58639275 A>G), RS1000043114 (15:58677683 T>A), RS1000075760 (15:58677256 T>A), RS1000118990 (15:58626074 T>G), RS1000153859 (15:58634356 G>A), RS1000171725 (15:58710817 T>C), RS1000189017 (15:58671354 C>T), RS1000210683 (15:58703191 T>A), RS1000268895 (15:58634582 C>A,G), RS1000273417 (15:58711341 C>G), RS1000286409 (15:58711113 T>C), RS1000290112 (15:58741271 G>A,T), RS1000304013 (15:58650247 A>G), RS1000316855 (15:58747131 T>C)

Disease associations

OMIM: gene MIM:602192 | disease phenotypes: MIM:615537, MIM:615590

GenCC curated gene-disease

Disease	Classification	Inheritance
reticulate acropigmentation of Kitamura	Strong	Autosomal dominant

Mondo (3): reticulate acropigmentation of Kitamura (MONDO:0014234), Alzheimer disease 18 (MONDO:0014265), corticobasal syndrome (MONDO:0018696)

Orphanet (2): Reticulate acropigmentation of Kitamura (Orphanet:178307), Corticobasal syndrome (Orphanet:454887)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000962	Hyperkeratosis
HP:0003621	Juvenile onset
HP:0011463	Childhood onset
HP:0012733	Macule

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST007201_191	Schizophrenia	4.000000e-08
GCST007201_459	Schizophrenia	8.000000e-06
GCST007320_74	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-09
GCST007321_15	Family history of Alzheimer’s disease	3.000000e-07
GCST007511_2	Alzheimer’s disease (late onset)	7.000000e-09
GCST007576_90	Chronotype	1.000000e-08
GCST007637_3	Diffusing capacity of carbon monoxide	4.000000e-06
GCST009391_1357	Metabolite levels	4.000000e-12
GCST009391_1374	Metabolite levels	5.000000e-06
GCST010241_418	Apolipoprotein A1 levels	1.000000e-12
GCST011065_10	Levodopa-induced dyskinesia in levodopa treated Parkinson’s disease	7.000000e-06
GCST90012877_5	Alzheimer’s disease or family history of Alzheimer’s disease	4.000000e-06
GCST90012877_6	Alzheimer’s disease or family history of Alzheimer’s disease	3.000000e-11

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0009268	family history of Alzheimer’s disease
EFO:1001870	late-onset Alzheimers disease
EFO:0008328	chronotype measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0010366	lysophosphatidylethanolamine 16:0 measurement
EFO:0010367	lysophosphatidylethanolamine 18:0 measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0010747	response to levodopa

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5028 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 12,321 (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
CHEMBL19611	ILOMASTAT	2	12,065
CHEMBL206815	APRATASTAT	2	256

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M12: Astacin/Adamalysin

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
ilomastat	Inhibition	8.09	pIC50
compound 25 [PMID: 18068976]	Inhibition	7.8	pIC50
GI254023X	Inhibition	5.28	pIC50

Binding affinities (BindingDB)

431 measured of 444 human assays (487 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(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
(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
marimastat	IC50	35.8 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
(2S)-N-hydroxy-2-[4-(2-methylpropanoyl)piperazin-1-yl]-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]propanamide	IC50	53 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-N-hydroxy-2-[4-[(4-methylphenyl)methyl]piperazin-1-yl]-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]propanamide	IC50	63 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
(2S)-2-[4-[(4-fluorophenyl)methyl]piperazin-1-yl]-N-hydroxy-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]propanamide	IC50	67 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
N-hydroxy-4-[4-(4-hydroxybut-2-ynoxy)phenyl]sulfonyl-2,2-dimethylthiomorpholine-3-carboxamide	IC50	71 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
(S)-N-hydroxy-4-(4-(4-hydroxybut-2-ynyloxy)phenylsulfonyl)-2,2-dimethylthiomorpholine-3-carboxamide	IC50	71 nM	US-9266848: 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
(2S)-N-hydroxy-2-[4-(2-methylpropylsulfonyl)piperazin-1-yl]-3-[[4-[(2-methylquinolin-4-yl)methoxy]phenyl]sulfonylamino]propanamide	IC50	86 nM	US-8633196: Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
3-({4-[(4-phenyl-1-piperazinyl)carbonyl]cyclohexyl}methyl)-2-thioxo-2,3-dihydro-4(1H)-quinazolinone	IC50	929 nM
4-but-2-ynoxy-N-[(2S)-3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]benzamide	IC50	942 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
1-(5-bromanylthiophen-2-yl)-2-[[5-[(2,3-dimethylphenyl)amino]-1,3,4-thiadiazol-2-yl]sulfanyl]ethanone	EC50	1410 nM
MLS000536683	IC50	2480 nM
MLS002474342	IC50	2580 nM
N-[(2S)-3-(hydroxyamino)-3-oxo-2-piperidin-1-ylpropyl]-4-(pyridin-4-ylmethoxy)benzamide	IC50	3090 nM	US-9266848: 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
5-chloro-7-((4-ethoxyphenyl)(pyridin-3-ylamino)methyl)quinolin-8-ol	IC50	3350 nM
3-(2,2-dimethylpropanoylamino)-N-(4-methoxyphenyl)-1-benzofuran-2-carboxamide	EC50	3410 nM
(5E)-5-[[4-(4-methylphenyl)-2-thiophen-2-yl-4H-1-benzopyran-3-yl]methylidene]-2-sulfanylidene-4-thiazolidinone	IC50	3630 nM
SMR000242949	IC50	4380 nM
2-cyclohexyl-N-(1H-1,2,4-triazol-5-yl)acetamide	EC50	4450 nM
2-[[3-(2-methylphenyl)-4-oxo-2-quinazolinyl]thio]-N-[(E)-[(E)-3-(2-nitrophenyl)prop-2-enylidene]amino]acetamide	IC50	4510 nM
1-({6-[(cyanomethyl)thio]benzimidazo[1,2-c]quinazolin-3-yl}carbonyl)piperidine-4-carboxamide	EC50	4620 nM
2-[(4-bromophenyl)-[5-keto-3-methyl-1-(5-phenylthiazol-2-yl)-3-pyrazolin-4-yl]methyl]malononitrile	IC50	4670 nM
2-(2-bromanyl-4-methyl-phenoxy)-N-(1H-1,2,4-triazol-5-yl)ethanamide	EC50	4930 nM
cid_845855	IC50	5200 nM
MLS002319865	IC50	5380 nM
N-[(2S)-3-(hydroxyamino)-2-(4-methylsulfonylpiperazin-1-yl)-3-oxopropyl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide	IC50	5800 nM	US-9115102: N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
(2S)-2-[[(4-methoxyphenyl)methyl-[(2S)-4-methyl-1-oxidanyl-pentan-2-yl]sulfamoyl]-(phenylmethyl)amino]-4-methyl-pentan-1-ol	IC50	5930 nM
N-[(2S)-3-(hydroxyamino)-3-oxo-2-piperidin-1-ylpropyl]-4-[(2-methylquinolin-4-yl)methoxy]benzamide	IC50	6400 nM	US-9266848: 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
2-(2,4-diketo-3-phenyl-thiazolidin-5-yl)-N-phenyl-acetamide	EC50	6420 nM
cid_44201804	IC50	6930 nM
1-(3,4-difluorophenyl)-1-[4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]ethanol	IC50	7590 nM
2-[(4-Cyclohexylsulfamoyl-benzenesulfonyl)-thiophen-2-ylmethyl-amino]-N-phenyl-acetamide	IC50	7690 nM
cid_25010880	IC50	7720 nM
cid_51361581	IC50	7720 nM
cid_44201827	IC50	7720 nM
SMR000628049	IC50	7720 nM
1-(4-methoxyphenyl)-3-[(2S,3R)-3-methyl-2-[[methyl(thiophen-2-ylsulfonyl)amino]methyl]-6-oxidanylidene-5-[(2S)-1-oxidanylpropan-2-yl]-3,4-dihydro-2H-1,5-benzoxazocin-8-yl]urea	IC50	7720 nM
2-[(4-chlorophenyl)methyl-(4-methylphenyl)sulfonylamino]-N-(2-furanylmethyl)benzamide	IC50	7720 nM
2-[(4-bromo-2-methylphenyl)thio]acetic acid [2-[4-(diethylamino)anilino]-2-oxoethyl] ester;sulfuric acid	IC50	7720 nM
MLS002548518	IC50	7720 nM
methyl (3R,4aR,5R,7S)-5-cyclopropyl-1-(naphthalen-1-ylmethyl)-2-oxo-3-[2-oxo-2-(4-phenylbutylamino)ethyl]-7-propan-2-yl-3,4,5,7-tetrahydropyrano[4,3-b]pyridine-4a-carboxylate	IC50	7720 nM
N-(3-chlorophenyl)-5-({[2-(4-chlorophenyl)ethyl]amino}sulfonyl)-2-fluorobenzamide	IC50	7720 nM
cid_1076245	IC50	7720 nM
MLS000562060	IC50	7720 nM
4,5-Dichloro-isothiazole-3-carboxylic acid (cyclopentylcarbamoyl-p-tolyl-methyl)-(4-methoxy-benzyl)-amide	IC50	7720 nM
N-[3-(fluoren-9-ylideneamino)oxy-2-oxidanyl-propyl]-4-methyl-N-(3-oxidanylpropyl)benzenesulfonamide	IC50	7720 nM
(6Z)-3-methoxy-2-methyl-6-[5-methyl-4-(1-phenylpyrazol-4-yl)-1,2-dihydropyrazol-3-ylidene]cyclohexa-2,4-dien-1-one	IC50	7720 nM
1-cycloheptyl-3-(4-phenylazanylphenyl)thiourea	IC50	7720 nM

ChEMBL bioactivities

248 potent at pChembl≥5 of 267 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.28	IC50	5.3	nM	CHEMBL4435465
8.28	IC50	5.3	nM	CHEMBL5206579
8.21	IC50	6.2	nM	CHEMBL442432
8.19	IC50	6.5	nM	CHEMBL253021
8.15	IC50	7.1	nM	CHEMBL251820
8.11	IC50	7.8	nM	CHEMBL400528
8.09	IC50	8.1	nM	ILOMASTAT
8.05	IC50	9	nM	CHEMBL569388
8.04	IC50	9.2	nM	CHEMBL3770688
8.04	IC50	9.1	nM	CHEMBL253021
8.02	IC50	9.6	nM	CHEMBL584116
8.00	IC50	10	nM	CHEMBL251820
7.96	IC50	11	nM	CHEMBL253230
7.96	IC50	11	nM	CHEMBL254492
7.96	IC50	11	nM	CHEMBL572301
7.96	IC50	11	nM	CHEMBL566233
7.92	IC50	12	nM	CHEMBL253665
7.92	IC50	12	nM	CHEMBL570760
7.89	IC50	13	nM	CHEMBL375418
7.89	IC50	13	nM	CHEMBL400528
7.89	IC50	13	nM	CHEMBL399351
7.85	IC50	14	nM	CHEMBL251847
7.85	IC50	14	nM	CHEMBL439405
7.85	IC50	14	nM	CHEMBL253665
7.85	IC50	14	nM	CHEMBL576061
7.82	IC50	15	nM	CHEMBL253920
7.82	IC50	15	nM	CHEMBL399351
7.82	IC50	15	nM	CHEMBL496628
7.80	IC50	16	nM	CHEMBL253460
7.80	IC50	16	nM	CHEMBL252612
7.80	IC50	16	nM	CHEMBL442432
7.77	IC50	17	nM	CHEMBL569166
7.75	IC50	18	nM	CHEMBL373532
7.75	IC50	18	nM	CHEMBL252612
7.75	IC50	18	nM	CHEMBL252023
7.75	IC50	18	nM	CHEMBL253035
7.75	IC50	18	nM	CHEMBL585299
7.72	IC50	19	nM	CHEMBL442443
7.72	IC50	19	nM	CHEMBL403185
7.72	IC50	19	nM	CHEMBL398743
7.72	IC50	19	nM	CHEMBL253020
7.72	IC50	19	nM	CHEMBL495596
7.70	IC50	20	nM	CHEMBL585886
7.70	IC50	20	nM	CHEMBL584334
7.68	IC50	21	nM	CHEMBL496829
7.66	IC50	22	nM	CHEMBL434567
7.66	IC50	22	nM	CHEMBL404409
7.66	IC50	22	nM	CHEMBL439405
7.66	IC50	22	nM	CHEMBL1287851
7.64	IC50	23	nM	CHEMBL375418

PubChem BioAssay actives

238 with measured affinity, of 352 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
(2R)-2-[(1S)-1-[acetyl(hydroxy)amino]ethyl]-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-5-phenylpentanamide	1628279: Inhibition of ADAM10 (unknown origin) assessed as blockage of TNF-alpha shedding	ic50	0.0053	uM
N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide	1895849: Inhibition of human ADAM10 using (biotin-SPLAQAVRSSSRTP(3H)S-NH2) as a substrate by streptavidin-coated scintillation proximity assay	ic50	0.0053	uM
(2-hydroxycyclopentyl) 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0062	uM
[(2S)-pyrrolidin-2-yl]methyl 4-[[4-(4-cyano-2-methylphenyl)piperidin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0065	uM
[(3S)-oxolan-3-yl] 4-(hydroxycarbamoyl)-4-[(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0071	uM
pyrrolidin-3-yl 4-[[4-(4-cyano-2-methylphenyl)piperidin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0078	uM
(2R)-N’-hydroxy-N-[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide	241679: In vitro inhibition of A disintegrin and metalloprotease domain 10 (ADAM10)	ic50	0.0081	uM
[(5S,6S)-5-(hydroxycarbamoyl)-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)piperidin-3-yl] pyrrolidine-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0090	uM
benzyl N-[(4R)-4-[[4-(4-cyano-2-methylphenyl)piperazin-1-yl]sulfonylamino]-5-(hydroxyamino)-5-oxopentyl]carbamate	1281791: Inhibition of recombinant human ADAM-10 using Mca-Lys-Pro-Leu-Gly-Leu-Dap(Dnp)-Ala-Arg-NH2 as substrate after 1 hr by fluorometric assay	ic50	0.0092	uM
[(3S,5S,6S)-5-(hydroxycarbamoyl)-1-methyl-6-(4-phenylpiperazine-1-carbonyl)piperidin-3-yl] piperidine-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0096	uM
(3-methyloxolan-3-yl) 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0110	uM
[(2R)-pyrrolidin-2-yl]methyl 4-[[4-(4-cyano-2-methylphenyl)piperidin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0110	uM
propan-2-yl N-[(5S,6S)-5-(hydroxycarbamoyl)-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)piperidin-3-yl]-N-methylcarbamate	447376: Inhibition of ADAM-10	ic50	0.0110	uM
[(3S,5S,6S)-5-(hydroxycarbamoyl)-6-(4-phenylpiperazine-1-carbonyl)piperidin-3-yl] pyrrolidine-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0110	uM
[(3S)-oxolan-3-yl] 4-[[4-(4-cyano-2-methylphenyl)piperidin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0120	uM
(2S,3S)-5-[benzoyl(methyl)amino]-N-hydroxy-2-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)piperidine-3-carboxamide	447376: Inhibition of ADAM-10	ic50	0.0120	uM
(6S,7S)-N-hydroxy-6-(3-phenyl-2,5-dihydropyrrole-1-carbonyl)-5-azaspiro[2.5]octane-7-carboxamide	313636: Inhibition of HER2 sheddase in BT474 cells by extracellular domain shedding assay	ic50	0.0130	uM
[(3S)-oxolan-3-yl] 4-(hydroxycarbamoyl)-4-[(4-phenylpiperazin-1-yl)sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0130	uM
(4,4-dimethyloxolan-3-yl) 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0140	uM
(6S,7S)-6-[4-(3-chlorophenyl)piperazine-1-carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide	313637: Binding affinity to ADAM10	ic50	0.0140	uM
(2S,3S)-N-hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-[(3R)-3-phenylpyrrolidine-1-carbonyl]piperidine-3-carboxamide	447376: Inhibition of ADAM-10	ic50	0.0140	uM
(6S,7S)-6-[4-(3,5-difluorophenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-N-hydroxy-5-azaspiro[2.5]octane-7-carboxamide	313637: Binding affinity to ADAM10	ic50	0.0150	uM
(1S,2S,5S)-N-hydroxy-5-(2-oxo-2-piperidin-1-ylethyl)-2-(4-phenylpiperazine-1-carbonyl)cyclohexane-1-carboxamide	375733: Inhibition of human recombinant ADAM10	ic50	0.0150	uM
pyrrolidin-3-yl 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0160	uM
(6S,7S)-N-hydroxy-6-[4-(3-propan-2-ylphenyl)piperidine-1-carbonyl]-5-azaspiro[2.5]octane-7-carboxamide	313637: Binding affinity to ADAM10	ic50	0.0160	uM
(2S,3S)-N-hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)piperidine-3-carboxamide	447376: Inhibition of ADAM-10	ic50	0.0170	uM
[(3S)-oxolan-3-yl] 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0180	uM
[(3S)-oxolan-3-yl] 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0180	uM
(6S,7S)-N-hydroxy-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-azaspiro[2.5]octane-7-carboxamide	313636: Inhibition of HER2 sheddase in BT474 cells by extracellular domain shedding assay	ic50	0.0180	uM
[(3S,5S,6S)-5-(hydroxycarbamoyl)-1-methyl-6-(4-phenylpiperazine-1-carbonyl)piperidin-3-yl] pyrrolidine-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0180	uM
[(2R)-pyrrolidin-2-yl]methyl 4-[[4-(4-cyano-2-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0190	uM
2-methylpropyl (6S,7S)-7-(hydroxycarbamoyl)-6-(4-phenyl-3,4-dihydro-2H-pyridine-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	313637: Binding affinity to ADAM10	ic50	0.0190	uM
methyl (6S,7S)-7-(hydroxycarbamoyl)-6-(4-phenylpiperidine-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	313637: Binding affinity to ADAM10	ic50	0.0190	uM
[(2R)-pyrrolidin-2-yl]methyl 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313836: Inhibition of ADAM10	ic50	0.0190	uM
(2S,3S)-N-hydroxy-5-(2-oxo-2-pyrrolidin-1-ylethyl)-2-(4-phenylpiperazine-1-carbonyl)piperidine-3-carboxamide	375733: Inhibition of human recombinant ADAM10	ic50	0.0190	uM
[(3S,5S,6S)-5-(hydroxycarbamoyl)-1-methyl-6-(4-phenylpiperazine-1-carbonyl)piperidin-3-yl] azetidine-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0200	uM
methyl (2S,3S,5S)-3-(hydroxycarbamoyl)-2-(4-phenylpiperazine-1-carbonyl)-5-(pyrrolidine-1-carbonyloxy)piperidine-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0200	uM
(1S,2S,5S)-N-hydroxy-5-(2-oxo-2-piperidin-1-ylethyl)-2-[4-(3-propan-2-ylphenyl)piperidine-1-carbonyl]cyclohexane-1-carboxamide	375733: Inhibition of human recombinant ADAM10	ic50	0.0210	uM
[(3S)-oxolan-3-yl] 4-(hydroxycarbamoyl)-4-[(4-phenylpiperidin-1-yl)sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0220	uM
methyl (6S,7S)-7-(hydroxycarbamoyl)-6-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	1235676: Inhibition of human ADAM10	ic50	0.0220	uM
(5R)-5-[(5-methoxy-3-oxo-1H-isoindol-2-yl)methyl]-5-(2-pyridin-3-ylethynyl)imidazolidine-2,4-dione	538184: Inhibition of ADAM10	ic50	0.0220	uM
[(2S)-pyrrolidin-2-yl]methyl 4-(hydroxycarbamoyl)-4-[[4-(2-methylphenyl)piperidin-1-yl]sulfonylmethyl]piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0230	uM
(2S,3S)-N-hydroxy-5-[methyl(2-methylpropanoyl)amino]-2-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)piperidine-3-carboxamide	447376: Inhibition of ADAM-10	ic50	0.0230	uM
[(3S)-oxolan-3-yl] 4-[[4-(4-cyano-2-methylphenyl)piperazin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0250	uM
(6S,7S)-N-hydroxy-6-[4-(3-methylphenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-5-azaspiro[2.5]octane-7-carboxamide	313637: Binding affinity to ADAM10	ic50	0.0250	uM
methyl (6S,7S)-7-(hydroxycarbamoyl)-6-(3-phenyl-2,5-dihydropyrrole-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	313637: Binding affinity to ADAM10	ic50	0.0260	uM
oxan-4-yl (6S,7S)-7-(hydroxycarbamoyl)-6-(4-phenylpiperazine-1-carbonyl)-5-azaspiro[2.5]octane-5-carboxylate	313636: Inhibition of HER2 sheddase in BT474 cells by extracellular domain shedding assay	ic50	0.0260	uM
[(3R)-oxolan-3-yl] 4-[[4-(4-cyano-2-methylphenyl)piperazin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	344625: Inhibition of ADAM10	ic50	0.0260	uM
[(3S,5S,6S)-5-(hydroxycarbamoyl)-1-methyl-6-(4-phenylpiperazine-1-carbonyl)piperidin-3-yl] azocane-1-carboxylate	447376: Inhibition of ADAM-10	ic50	0.0260	uM
[(2S)-pyrrolidin-2-yl]methyl 4-[[4-(4-cyano-2-methylphenyl)-3,6-dihydro-2H-pyridin-1-yl]sulfonylmethyl]-4-(hydroxycarbamoyl)piperidine-1-carboxylate	313835: Inhibition of HER2 sheddase in human BT474 cells	ic50	0.0270	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression, affects localization	4
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression, increases expression	4
bisphenol A	affects cotreatment, increases methylation, increases expression	2
sodium arsenite	affects methylation, decreases expression	2
cobaltous chloride	decreases expression	2
Air Pollutants	increases abundance, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
deoxynivalenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride	affects cotreatment, increases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
enzalutamide	affects expression	1
picoxystrobin	decreases expression	1
Bortezomib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Antimycin A	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Biological Products	decreases expression	1
Cadmium	increases abundance, increases palmitoylation, decreases reaction	1

ChEMBL screening assays

64 unique, capped per target: 60 binding, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001997	Binding	Inhibition of ADAM10	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
CHEMBL4018054	ADMET	Inhibition of recombinant human C-terminal His10-tagged ADAM10 expressed in baculovirus infected Sf21 cells using Abz-LANAVRSSSR-(DapDnp)-NH2 as substrate by fluorescence assay	First insight into structure-activity relationships of selective meprin β inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

12 cell lines: 7 cancer cell line, 5 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8AW	Abcam HCT 116 ADAM10 KO	Cancer cell line	Male
CVCL_B8S6	Abcam MCF-7 ADAM10 KO	Cancer cell line	Female
CVCL_B9CY	Abcam A-549 ADAM10 KO	Cancer cell line	Male
CVCL_D1RH	Abcam U-87MG ADAM10 KO	Cancer cell line	Male
CVCL_D7JJ	Ubigene A-549 ADAM10 KO	Cancer cell line	Male
CVCL_E4TR	KOLF2.1J ADAM10 PTC PTC/PTC	Induced pluripotent stem cell	Male
CVCL_E7JF	KOLF2.1J ADAM10 Q170H SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7JG	KOLF2.1J ADAM10 Q170H SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7JI	KOLF2.1J ADAM10 R181G SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7JJ	KOLF2.1J ADAM10 R181G SNV/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00273897	PHASE2	COMPLETED	Electrical Polarization of the Brain in Corticobasal Syndrome
NCT04734379	PHASE2	UNKNOWN	Rho Kinase (ROCK) Inhibitor in Tauopathies - 1
NCT05983588	PHASE2	ACTIVE_NOT_RECRUITING	PROFIL Study to Investigate the Effect of GPB on NfL Levels in Patients With Corticobasal Syndrome (CBS)
NCT06162013	PHASE2	RECRUITING	The NADAPT Study: a Randomized Double-blind Trial of NAD Replenishment Therapy for Atypical Parkinsonism
NCT02133846	PHASE1	COMPLETED	Safety Study of TPI-287 to Treat CBS and PSP
NCT04100889	Not specified	WITHDRAWN	A Non-Interventional Pilot Study to Explore the Role of Gut Flora in Alzheimer’s Disease
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)
NCT02365922	Not specified	COMPLETED	Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL)
NCT02964637	Not specified	RECRUITING	Diagnosing Frontotemporal Lobar Degeneration
NCT02966145	Not specified	COMPLETED	4-Repeat Tauopathy Neuroimaging Initiative - Cycle 2
NCT03552484	Not specified	COMPLETED	In-Home Care for Patients With PSP and Related Disorders
NCT04715399	Not specified	RECRUITING	UPenn Observational Research Repository on Neurodegenerative Disease
NCT05073471	Not specified	ACTIVE_NOT_RECRUITING	Music and Brain Stimulation for Upper Extremity Performance in Patients With Corticobasal Syndrome
NCT05653778	Not specified	RECRUITING	Scrambler Therapy for Corticobasal Syndrome-Associated Pain
NCT06224920	Not specified	COMPLETED	Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer’s Disease
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