ADAMTS4

Summary

ADAMTS4 (ADAM metallopeptidase with thrombospondin type 1 motif 4, HGNC:220) is a protein-coding gene on chromosome 1q23.3, encoding A disintegrin and metalloproteinase with thrombospondin motifs 4 (O75173). Cleaves aggrecan, a cartilage proteoglycan, at the ‘392-Glu-|-Ala-393’ site and may be involved in its turnover.

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of this family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 9507 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 159 total — 3 pathogenic, 1 likely-pathogenic
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005099

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:220
Approved symbol	ADAMTS4
Name	ADAM metallopeptidase with thrombospondin type 1 motif 4
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0688, ADAMTS-2, ADMP-1
Ensembl gene	ENSG00000158859
Ensembl biotype	protein_coding
OMIM	603876
Entrez	9507

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000367995, ENST00000367996, ENST00000478394, ENST00000926273, ENST00000926274, ENST00000960126, ENST00000960127

RefSeq mRNA: 2 — MANE Select: NM_005099 NM_001320336, NM_005099

CCDS: CCDS1223

Canonical transcript exons

ENST00000367996 — 9 exons

Exon	Start	End
ENSE00001041571	161193640	161193826
ENSE00001041575	161193213	161193388
ENSE00001041585	161192065	161192240
ENSE00001041589	161196557	161196880
ENSE00001041601	161193935	161194221
ENSE00001041604	161196171	161196303
ENSE00001288666	161195465	161195635
ENSE00001446083	161184302	161191564
ENSE00001860852	161197995	161199054

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 97.72.

FANTOM5 (CAGE): breadth broad, TPM avg 5.9929 / max 624.4813, expressed in 839 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15605	5.8265	828
15604	0.1664	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left uterine tube	UBERON:0001303	97.72	gold quality
omental fat pad	UBERON:0010414	94.84	gold quality
peritoneum	UBERON:0002358	94.70	gold quality
gall bladder	UBERON:0002110	93.63	gold quality
mucosa of stomach	UBERON:0001199	93.15	gold quality
left ovary	UBERON:0002119	92.98	gold quality
stromal cell of endometrium	CL:0002255	92.60	gold quality
right ovary	UBERON:0002118	91.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.89	gold quality
lower esophagus mucosa	UBERON:0035834	90.96	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.24	gold quality
right atrium auricular region	UBERON:0006631	89.92	gold quality
cardiac atrium	UBERON:0002081	88.75	gold quality
smooth muscle tissue	UBERON:0001135	88.14	gold quality
tibial nerve	UBERON:0001323	86.21	gold quality
vermiform appendix	UBERON:0001154	85.87	gold quality
spinal cord	UBERON:0002240	85.76	gold quality
left coronary artery	UBERON:0001626	85.62	gold quality
right lobe of thyroid gland	UBERON:0001119	85.53	gold quality
left lobe of thyroid gland	UBERON:0001120	85.52	gold quality
upper lobe of left lung	UBERON:0008952	84.78	gold quality
ascending aorta	UBERON:0001496	84.49	gold quality
thoracic aorta	UBERON:0001515	83.91	gold quality
ovary	UBERON:0000992	83.79	gold quality
gastrocnemius	UBERON:0001388	83.40	gold quality
thyroid gland	UBERON:0002046	83.39	gold quality
colonic epithelium	UBERON:0000397	82.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.74	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.70	gold quality
coronary artery	UBERON:0001621	82.53	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	1109.65
E-ENAD-27	yes	412.45
E-MTAB-8142	yes	46.26
E-GEOD-135922	yes	28.01
E-GEOD-83139	yes	8.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG, PPARG, SP1, STAT1, STAT3, TGFB1, ZNF384

miRNA regulators (miRDB)

93 targeting ADAMTS4, 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-8485	100.00	77.57	4731
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-670-5P	99.67	69.94	1565

Literature-anchored findings (GeneRIF, showing 40)

• activation of proteolytic activity by C-terminal truncation (PMID:11796708)
• Aggrecanase-1 is expressed by fibroblast-like synoviocytes from rheumatoid arthritis and osteoarthritis patients and is induced by cytokines, especially TGF-beta. (PMID:11801682)
• extracellular matrix degrading enzyme (PMID:11831030)
• has a specific cleavage site at the matrix metalloproteinase site in its interglobular domain (PMID:11854269)
• Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. (PMID:11956193)
• Autocatalytic cleavage reveals multiple glycosaminoglycan-binding sites (PMID:12202483)
• ADAMTS-2 metalloproteinase is shown to cleave procollagen III N-propeptides as effectively as those of procollagens I and II (PMID:12646579)
• Multiple forms of ADAMTS4 protein characterized by Western analysis in human brain tissue lead to the conclusion that the ‘aggrecanase’ group of the ADAMTS family (ADAMTS 1, 4, 5 and 9) is responsible for turnover of versican V2 in the adult brain. (PMID:14561220)
• ADAMTS-4 lacking the spacer domain has promiscuous substrate specificity considerably different from that previously reported for aggrecan core protein (PMID:14662755)
• ADAMTS-4 activation involves the coordinated activity of both glycosylphosphatidyl inositol-anchored MT4-MMP and the proteoglycan form of syndecan-1 on the cell surface (PMID:14701864)
• ADAMTS4 and ADAMTS5 are inhibited by alpha2-macroglobulin (PMID:14715656)
• pro-ADAMTS4 is cleaved by proprotein convertase furin in the trans-Golgi network (PMID:14744861)
• the aggrecanase activity of ADAMTS4 is inhibited by fibronectin through interaction with their C-terminal domains (PMID:15161923)
• ADAMTS4 and 5 are upregulated on proliferating glioblastoma cells, and these proteases may contribute to their invasive potential (PMID:16003758)
• Taken together, these data suggest that aggrecanase-1 and alpha1-antitrypsin bind in vivo, although the physiological significance of the interaction between aggrecanase-1 and alpha1-antitrypsin remains unclear. (PMID:16099106)
• The ADAMTS-4 promoter would serve as a valuable mechanistic tool to better understand the regulation of ADAMTS-4 expression by signaling pathways that modulate cartilage matrix breakdown. (PMID:16677612)
• analysis of osteoarthritic synovium using primers designed to amplify across the exon 8/9 junction resulted in amplification of the expected product and a smaller product missing 161 bp from the 5’ end of exon 9, the result of alternative splicing (PMID:16723216)
• Macrophages infiltrating granulation and adjacent disc tissues express ADAMTS-4, suggesting its involvement in herniated disc regression. (PMID:16741450)
• The inhibition of ADAMTS-2 by TIMP-3 alone out of 4 TIMP proteins is reported. (PMID:16771712)
• The induction of ADAMTS-4 by B burgdorferi results in the cleavage of aggrecan, which may be an important first step that leads to permanent degradation of cartilage. (PMID:17009305)
• analysis of aggrecanase (ADAMTS-4) conformation, affinity and sequence specificity (PMID:17095512)
• oncostatin M-stimulated ADAMTS-4 and matrix metallopeptidase 13 expression is mediated by extracellular signal-regulated kinases, Janus kinase 3/STAT1/3 and phosphatidylinositol 3-kinase/Akt and by cross talk between these pathways (PMID:17208315)
• Our data suggest that both ADAMTS-4 and ADAMTS-5 contribute to the structural damage that characterizes human osteoarthritis. (PMID:17265492)
• Inhibition of NF0kappaB results in the decreased expression of several destructive metalloproteinases and also the ADAMTS4 aggrecanase (PMID:17295438)
• recombinant ADAMTS-4 effectively cleaved intact matrilin-3 at the predicted motif at Glu435/Ala436 generating two species of 45 and 5 kDa (PMID:17311924)
• ADAMTS-5 is a major aggrecanase in cartilage metabolism and pathology, with aggrecanase activity at least 1,000-fold greater than that of ADAMTS-4 under physiological conditions (PMID:17430884)
• TIMP-3 inhibition of ADAMTS-4 is modulated by interactions between aggrecan and the C-terminal domain of ADAMTS-4 (PMID:17470431)
• ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques. (PMID:17606262)
• In both nucleus pulposis and anulus fibrosus, ADAMTS4 was higher in discs with a higher level of degeneration. Aggrecan fragmentation profile analysis showed the involvement of aggrecanases and other proteases during disc degeneration. (PMID:17978660)
• after stimulation, the protease activity of PC5A is enhanced, as evidenced by the cleavage of the PC5A substrates Lefty, ADAMTS-4, endothelial lipase, and PCSK9. (PMID:18039650)
• Crystal structures of the two most active human aggrecanase isoforms, ADAMTS4 and ADAMTS5, each in complex with bound inhiitor. (PMID:18042673)
• PKCzeta is involved in regulation of IL-1beta-induced NF-kappaB signaling in human osteoarthritis chondrocytes, which regulates downstream expression of ADAMTS-4 and NOS2 via NF-kappaB. (PMID:18050214)
• the catalytic domain of ADAMTS-5 has higher intrinsic catalytic ability than that of ADAMTS-4 (PMID:18156631)
• Human ADAMTS-4 was expressed in rodent pyramidal neurons and neuropil of stratum oriens and the lacunosum moleculare. (PMID:18221525)
• Both ADAMTS-4 mRNA and protein processing may be differentially regulated in normal and damaged tendons. (PMID:18387286)
• PACE4 is a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage; posttranslational activation of ADAMTS-4 and ADAMTS-5 in the extracellular milieu of cartilage results in aggrecan degradation (PMID:18671934)
• Expression of ADAMTS4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-de-methylation. (PMID:18941754)
• findings suggest that Ras, ROS along with MyD88, IRAK1, or TRAF6 synergistically mediate ADAMTS-4 regulation by IL1-beta (PMID:19342688)
• The C-terminal domains of ADAMTS-4 and ADAMTS-5 affect the structure around the active site, favouring interaction with TIMP-3. (PMID:19643179)
• Plasma ADAMTS4 was measured in stable-effort angina pectoris, acute coronary syndrome & controls. The pattern of its release was clearly different in various forms of ACS. It showed a weak correlation with high-sensitivity C-reactive protein. (PMID:19944557)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Adamts4	ENSMUSG00000006403
rattus_norvegicus	Adamts4	ENSRNOG00000003538

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), ADAMTS10 (ENSG00000142303), ADAMTSL4 (ENSG00000143382), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS13 (ENSG00000160323), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 4 — O75173 (reviewed: O75173)

Alternative names: ADMP-1, Aggrecanase-1

All UniProt accessions (2): O75173, Q5VTW1

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves aggrecan, a cartilage proteoglycan, at the ‘392-Glu-|-Ala-393’ site and may be involved in its turnover. Also cleaves COMP. May play an important role in the destruction of aggrecan in arthritic diseases. Could be a critical factor in the exacerbation of neurodegeneration in Alzheimer disease.

Subunit / interactions. Interacts with SRPX2.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in brain, lung and heart. Expressed at very low level in placenta and skeletal muscles. Isoform 2: Detected in osteoarthritic synovium.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Glycosylated. Can be O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS family members. Can also be C-glycosylated with one or two mannose molecules on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and N-glycosylated. These other glycosylations can also facilitate secretion.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The spacer domain and the TSP type-1 domains are important for a tight interaction with the extracellular matrix. The spacer domain is also required for cleavage of COMP. 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. By IL1/interleukin-1.

Miscellaneous. Functional aggrecanase.

Isoforms (2)

UniProt ID	Names	Canonical?
O75173-1	1	yes
O75173-2	2, ADAMTS4_v1

RefSeq proteins (2): NP_001307265, NP_005090* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR041645	ADAMTS_CR_2	Domain
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF01421, PF05986, PF17771, PF19236

UniProt features (65 total): strand 15, disulfide bond 11, helix 10, sequence variant 8, binding site 4, turn 4, domain 3, sequence conflict 2, signal peptide 1, propeptide 1, glycosylation site 1, chain 1, splice variant 1, region of interest 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4WK7	X-RAY DIFFRACTION	1.24
4WKI	X-RAY DIFFRACTION	1.6
4WKE	X-RAY DIFFRACTION	1.62
2RJP	X-RAY DIFFRACTION	2.8
3B2Z	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75173-F1	80.80	0.45

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): 362

Ligand- & substrate-binding residues (4): 361; 365; 371; 194 (in inhibited form)

Disulfide bonds (11): 293–345, 322–327, 339–423, 377–407, 449–472, 460–482, 467–501, 495–506, 532–569, 536–574, 547–559

Glycosylation sites (1): 68

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins
R-HSA-1474244	Extracellular matrix organization
R-HSA-1643685	Disease
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 174 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, LFA1_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, FOSTER_TOLERANT_MACROPHAGE_UP, MARTINEZ_RB1_TARGETS_DN, GROSS_ELK3_TARGETS_DN, TGCTGAY_UNKNOWN, GGCAGTG_MIR3243P, LYF1_01

GO Biological Process (6): skeletal system development (GO:0001501), proteolysis (GO:0006508), extracellular matrix disassembly (GO:0022617), proteoglycan catabolic process (GO:0030167), extracellular matrix organization (GO:0030198), defense response to bacterium (GO:0042742)

GO Molecular Function (8): protease binding (GO:0002020), metalloendopeptidase activity (GO:0004222), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nuclear speck (GO:0016607), extracellular matrix (GO:0031012), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Extracellular matrix organization	1
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
system development	1
protein metabolic process	1
cellular component disassembly	1
extracellular matrix organization	1
proteoglycan metabolic process	1
glycoprotein catabolic process	1
extracellular structure organization	1
external encapsulating structure organization	1
defense response	1
response to bacterium	1
enzyme binding	1
endopeptidase activity	1
metallopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
transition metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
nuclear ribonucleoprotein granule	1
external encapsulating structure	1

Protein interactions and networks

STRING

1440 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS4	ACAN	P16112	970
ADAMTS4	MMP13	P45452	900
ADAMTS4	MMP3	P08254	859
ADAMTS4	COL10A1	Q03692	838
ADAMTS4	COL1A1	P02452	802
ADAMTS4	FN1	P02751	800
ADAMTS4	COL1A2	P02464	798
ADAMTS4	TIMP3	P35625	781
ADAMTS4	TIMP1	P01033	757
ADAMTS4	FURIN	P09958	756
ADAMTS4	EFEMP2	O95967	724
ADAMTS4	COL2A1	P02458	719
ADAMTS4	BGN	P13247	706
ADAMTS4	FBLN5	Q9UBX5	705
ADAMTS4	SRPX2	O60687	700

IntAct

18 interactions, top by confidence:

A	B	Type	Score
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
ADAMTS4		psi-mi:“MI:0194”(cleavage reaction)	0.440
ADAMTS4	ZBTB16	psi-mi:“MI:0915”(physical association)	0.440
ADAMTS4	ZBTB16	psi-mi:“MI:0403”(colocalization)	0.440
NSUN3	ADAMTS4	psi-mi:“MI:0915”(physical association)	0.400
YTHDC1	ADAMTS4	psi-mi:“MI:0915”(physical association)	0.370
CCDC33	PRMT5	psi-mi:“MI:0914”(association)	0.350
	CCN1	psi-mi:“MI:0914”(association)	0.350
ADAMTS4	RAD51B	psi-mi:“MI:0914”(association)	0.350
HMGCLL1	ADAMTS4	psi-mi:“MI:0914”(association)	0.350
	NFIB	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH5	MYO1C	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (84): ADAMTS4 (Affinity Capture-MS), TUBB1 (Affinity Capture-MS), ADAMTS4 (Affinity Capture-MS), XIAP (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), KIAA0232 (Affinity Capture-MS), DICER1 (Affinity Capture-MS), LOXL2 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), RAD51B (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), ITPA (Affinity Capture-MS)

ESM2 similar proteins: A0JND9, E1BPW0, O14773, O18956, O35795, O55026, O75173, O75355, O75356, O75578, O89023, O93295, P08514, P08648, P11688, P17405, P49961, P55772, P56201, P79784, P97687, Q04519, Q0VD19, Q12794, Q32M88, Q49HH9, Q49KI5, Q5DRK1, Q5IS74, Q5MY95, Q5RFL1, Q5RFQ8, Q60HH1, Q6P3E7, Q6P6S9, Q717C1, Q717C2, Q7RTX0, Q8BFW6, Q8BNJ2

Diamond homologs: A2VEC9, A6QNY1, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, O08721, O08722, O08747, O14514, O15072, O55225, O60241, O60242, O75173, O88783, O95185, O95450, P04275, P07358, P07996, P27918, P35441, P35442, P35448, P55314, P57110, P58397, P58459, P59384, P79331, P80012, P97857, P98088, P98092, P98160, P98164

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ADAMTS4	“down-regulates quantity by destabilization”	ACAN	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	133
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1527326	GRCh37/hg19 1q23.2-24.1(chr1:160417296-166197042)	Pathogenic
57465	GRCh38/hg38 1q23.2-24.1(chr1:159479887-166895086)x1	Pathogenic
625771	GRCh37/hg19 1q23.2-25.1(chr1:160369890-175796325)	Pathogenic
1341040	GRCh37/hg19 1q23.3(chr1:160859558-161409185)x3	Likely pathogenic

SpliceAI

1255 predictions. Top by Δscore:

Variant	Effect	Δscore
1:161191143:T:TA	donor_gain	1.0000
1:161192060:AGAAC:A	donor_loss	1.0000
1:161192061:GAAC:G	donor_loss	1.0000
1:161192062:AACCT:A	donor_loss	1.0000
1:161192063:A:AT	donor_loss	1.0000
1:161192064:C:CA	donor_loss	1.0000
1:161192068:AATTT:A	donor_gain	1.0000
1:161192072:T:A	donor_gain	1.0000
1:161192141:T:TA	donor_gain	1.0000
1:161192144:T:TA	donor_gain	1.0000
1:161193211:AC:A	donor_gain	1.0000
1:161193212:CC:C	donor_gain	1.0000
1:161193384:CAGGG:C	acceptor_gain	1.0000
1:161193385:AGGG:A	acceptor_gain	1.0000
1:161193386:GGG:G	acceptor_gain	1.0000
1:161193387:GG:G	acceptor_gain	1.0000
1:161193388:GC:G	acceptor_loss	1.0000
1:161193389:C:CA	acceptor_loss	1.0000
1:161193389:C:CC	acceptor_gain	1.0000
1:161193390:T:A	acceptor_loss	1.0000
1:161193636:TCA:T	donor_loss	1.0000
1:161193637:CA:C	donor_loss	1.0000
1:161193639:C:CA	donor_loss	1.0000
1:161193822:GGAAT:G	acceptor_gain	1.0000
1:161193824:AAT:A	acceptor_gain	1.0000
1:161193825:AT:A	acceptor_gain	1.0000
1:161193827:C:CC	acceptor_gain	1.0000
1:161193838:C:CT	acceptor_gain	1.0000
1:161193933:A:AC	donor_gain	1.0000
1:161193934:C:CC	donor_gain	1.0000

AlphaMissense

5371 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:161194068:C:G	C472S	1.000
1:161194069:A:T	C472S	1.000
1:161194137:C:G	C449S	1.000
1:161194138:A:T	C449S	1.000
1:161193268:C:G	C619S	0.999
1:161193269:A:T	C619S	0.999
1:161193306:C:A	W606C	0.999
1:161193306:C:G	W606C	0.999
1:161193699:C:G	C559S	0.999
1:161193700:A:T	C559S	0.999
1:161193806:C:A	W523C	0.999
1:161193806:C:G	W523C	0.999
1:161194038:C:G	C482S	0.999
1:161194039:A:T	C482S	0.999
1:161194067:G:C	C472W	0.999
1:161194068:C:T	C472Y	0.999
1:161194069:A:G	C472R	0.999
1:161194070:C:A	W471C	0.999
1:161194070:C:G	W471C	0.999
1:161194124:G:C	F453L	0.999
1:161194124:G:T	F453L	0.999
1:161194125:A:C	F453C	0.999
1:161194126:A:G	F453L	0.999
1:161194136:G:C	C449W	0.999
1:161194137:C:A	C449F	0.999
1:161194137:C:T	C449Y	0.999
1:161194138:A:G	C449R	0.999
1:161195502:A:C	S408R	0.999
1:161195502:A:T	S408R	0.999
1:161195504:T:G	S408R	0.999

dbSNP variants (sampled 300 via entrez): RS1000246082 (1:161186326 G>C), RS1000323253 (1:161193762 C>A,T), RS1000464493 (1:161184985 C>T), RS1000470549 (1:161192886 G>A,C), RS1000550277 (1:161199368 G>A), RS1000562237 (1:161184692 G>A), RS1000756366 (1:161193223 A>T), RS1000759389 (1:161192977 G>A), RS1000771680 (1:161185312 G>A,C), RS1000852820 (1:161198252 T>C), RS1000905157 (1:161198500 G>A), RS1000963834 (1:161198002 C>T), RS1000987613 (1:161199714 A>G), RS1001182443 (1:161196947 C>T), RS1001236405 (1:161197189 C>T)

Disease associations

OMIM: gene MIM:603876 | disease phenotypes: MIM:605373, MIM:606764

GenCC curated gene-disease

Mondo (2): pheochromocytoma/paraganglioma syndrome 3 (MONDO:0011544), gastrointestinal stromal tumor (MONDO:0011719)

Orphanet (2): Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Gastrointestinal stromal tumor (Orphanet:44890)

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST003987_12	Asthma	5.000000e-15
GCST004609_186	Monocyte percentage of white cells	6.000000e-11
GCST007320_68	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-10
GCST007321_16	Family history of Alzheimer’s disease	7.000000e-08
GCST008916_64	Asthma	2.000000e-08
GCST009720_86	Asthma	1.000000e-09
GCST010242_189	HDL cholesterol levels	5.000000e-08
GCST90002381_6	Eosinophil count	9.000000e-16
GCST90002382_14	Eosinophil percentage of white cells	5.000000e-09
GCST90002394_87	Monocyte percentage of white cells	7.000000e-21

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308
C565335	Paragangliomas 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2318 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 87,897 (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
CHEMBL279785	MARIMASTAT	3	29,447
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL19611	ILOMASTAT	2	12,065
CHEMBL4650334	ALDUMASTAT	2	58

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 15c [PMID: 21536437]	Inhibition	8.92	pIC50

Binding affinities (BindingDB)

328 measured of 363 human assays (363 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-((2S,4S)-1-(4-(4-fluoro-2-methylphenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.18 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-[(2S,4S)-1-({4-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]piperidin-1-yl}sulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	IC50	0.26 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(4-chloro-2-methylphenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.36 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-(2,5-dimethylpyridin-4-yl)ethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.43 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-chloro-4-(trifluoromethyl)phenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.48 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-bromo-4-fluorophenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.48 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2,5-dimethylphenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.48 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-1-(4-(2-methyl-4-(trifluoromethyl)phenethyl)piperidin-1-ylsulfonyl)pentan-2-yl)-N-hydroxyformamide	IC50	0.49 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(4-fluoro-2-(trifluoromethyl)phenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.52 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-chloro-4-(methylsulfonyl)phenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.57 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-(4,6-dimethylpyridin-3-yl)ethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.68 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-cyclopropyl-4-(trifluoromethyl)phenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	0.94 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2,4-dichlorobenzyloxy)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)pentan-2-yl)-N-hydroxyformamide	IC50	1 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2,4-dichlorophenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	1.1 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-(cyclobutanecarbonyl)-4-((4-(2-methyl-4-(trifluoromethyl)phenethyl)piperidin-1-ylsulfonyl)methyl)piperidin-4-yl)-N-hydroxyformamide	IC50	1.2 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(4-chloro-2-methylphenethyl)piperidin-1-ylsulfonyl)methyl)-1-(cyclobutanecarbonyl)piperidin-4-yl)-N-hydroxyformamide	IC50	1.2 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
4-chloro-N-[(3,3-difluoro-1-hydroxy-5-methylcyclohexyl)methyl]-1-(2,2,2-trifluoroethyl)indole-3-carboxamide	IC50	1.4 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(2-cyclopropyl-4-(methylsulfonyl)phenethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	1.4 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-(2,5-dimethylpyridin-3-yl)ethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	1.9 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-(cyclobutanecarbonyl)-4-((4-(4-fluoro-2-methylphenethyl)piperidin-1-ylsulfonyl)methyl)piperidin-4-yl)-N-hydroxyformamide	IC50	1.9 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-1-(4-(2-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)ethyl)piperidin-1-ylsulfonyl)pentan-2-yl)-N-hydroxyformamide	IC50	2.1 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(4-chloro-2-methylphenethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	2.7 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-chloro-5-fluorophenethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	2.8 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2,4-dichlorobenzyloxy)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	3.5 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2,4-dichlorophenethyl)piperazin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	3.8 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-(cyclobutanecarbonyl)-4-((4-(2-methylphenethyl)piperidin-1-ylsulfonyl)methyl)piperidin-4-yl)-N-hydroxyformamide	IC50	4.1 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	4.2 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(4-fluoro-2-methylphenethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	4.5 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
(3S)-4-{[4-(but-2-yn-1-yloxy)benzene]sulfonyl}-N-hydroxy-2,2-dimethylthiomorpholine-3-carboxamide	IC50	4.7 nM
N-((2S,4S)-1-(4-(2-(1,3-dimethyl-1H-pyrazol-5-yl)ethyl)piperidin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	5.4 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-hydroxy-N-(4-((4-(2-methylphenethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)formamide	IC50	5.6 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-hydroxy-N-(4-((4-(2-methyl-4-(methylsulfonyl)phenethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)formamide	IC50	5.8 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-((2S,4S)-1-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl)-N-hydroxyformamide	IC50	7.3 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-(cyclobutanecarbonyl)-4-((4-(4-fluoro-2-(trifluoromethyl)phenethyl)piperidin-1-ylsulfonyl)methyl)piperidin-4-yl)-N-hydroxyformamide	IC50	8.7 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	9.7 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-(cyclobutanecarbonyl)-4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)piperidin-4-yl)-N-hydroxyformamide	IC50	10 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-(azetidine-1-carbonyl)-4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)piperidin-4-yl)-N-hydroxyformamide	IC50	11 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(2-(3,5-dimethylisothiazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	13 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-{4-[2-(3,5-Dimethyl-isoxazol-4-yl)-ethyl]-piperidine-1-sulfonylmethyl}-1,1-dioxo-hexahydro-1lambda6-thiopyran-4-yl)-N-hydroxy-formamide	IC50	16 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(2-(2,5-dimethylpyridin-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	18 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)-1-methylpiperidin-4-yl)-N-hydroxyformamide	IC50	19 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)-4,4-difluorocyclohexyl)-N-hydroxyformamide	IC50	20 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(1-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)cyclohexyl)-N-hydroxyformamide	IC50	20 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
CGS 27023	KI	20 nM
4-[[4-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]piperidin-1-yl]sulfonylmethyl]-4-[formyl(hydroxy)amino]piperidine-1-carboxamide	IC50	24 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
N-(4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)-N-hydroxyformamide	IC50	26 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
(2R)-3-methyl-2-[(4-{4-[(3-methyl-1-benzofuran-2-yl)methoxy]phenyl}benzene)sulfonamido]butanoic acid	IC50	28 nM
N-(4-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)-1-(methylsulfonyl)piperidin-4-yl)-N-hydroxyformamide	IC50	29 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure
Inhibitor, 18	KI	47 nM
N-(1-((4-(2-(3,5-dimethylisoxazol-4-yl)ethyl)piperidin-1-ylsulfonyl)methyl)cycloheptyl)-N-hydroxyformamide	IC50	48 nM	US-10322143: Inhibitors of ADAMTS4 or ADAMTS5 for use in preventing or treating cardiac remodeling and chronic heart failure

ChEMBL bioactivities

381 potent at pChembl≥5 of 421 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.74	IC50	0.18	nM	CHEMBL1683454
9.59	IC50	0.26	nM	CHEMBL1615187
9.59	IC50	0.26	nM	CHEMBL1683460
9.44	IC50	0.36	nM	CHEMBL1683450
9.37	IC50	0.43	nM	CHEMBL1683458
9.32	IC50	0.48	nM	CHEMBL1683449
9.32	IC50	0.48	nM	CHEMBL1683451
9.32	IC50	0.48	nM	CHEMBL1683457
9.31	IC50	0.49	nM	CHEMBL1683455
9.28	IC50	0.52	nM	CHEMBL1683453
9.24	IC50	0.57	nM	CHEMBL1683464
9.17	IC50	0.68	nM	CHEMBL1683461
9.16	IC50	0.69	nM	CHEMBL1615187
9.03	IC50	0.94	nM	CHEMBL1683456
9.00	IC50	1	nM	CHEMBL187092
9.00	IC50	1	nM	CHEMBL4066965
9.00	IC50	1	nM	CHEMBL1683444
8.96	IC50	1.1	nM	CHEMBL1683447
8.96	IC50	1.1	nM	CHEMBL179552
8.92	IC50	1.2	nM	CHEMBL1784369
8.92	IC50	1.2	nM	CHEMBL1784371
8.85	IC50	1.4	nM	CHEMBL5875518
8.85	IC50	1.4	nM	CHEMBL1784359
8.85	IC50	1.4	nM	CHEMBL1683443
8.72	IC50	1.9	nM	CHEMBL1683459
8.72	IC50	1.9	nM	CHEMBL1784336
8.70	IC50	2	nM	CHEMBL4066965
8.70	IC50	2	nM	CHEMBL4072836
8.70	IC50	2	nM	CHEMBL3980860
8.68	IC50	2.1	nM	CHEMBL1683463
8.57	IC50	2.7	nM	CHEMBL1784358
8.55	IC50	2.8	nM	CHEMBL1683452
8.52	IC50	3	nM	CHEMBL187092
8.52	IC50	3	nM	CHEMBL24398
8.52	IC50	3	nM	CHEMBL3358156
8.46	IC50	3.5	nM	CHEMBL1615186
8.42	IC50	3.8	nM	CHEMBL1683446
8.40	IC50	4	nM	CHEMBL3358158
8.40	IC50	4	nM	CHEMBL4102193
8.40	IC50	4	nM	CHEMBL4450729
8.40	IC50	4	nM	CHEMBL4436740
8.40	IC50	4	nM	CHEMBL1078281
8.39	IC50	4.1	nM	CHEMBL1784337
8.38	IC50	4.2	nM	CHEMBL1683462
8.35	IC50	4.5	nM	CHEMBL1784339
8.30	IC50	5	nM	CHEMBL3358156
8.27	IC50	5.4	nM	CHEMBL1683465
8.25	IC50	5.6	nM	CHEMBL1784363
8.24	IC50	5.8	nM	CHEMBL1784360
8.22	IC50	6	nM	CHEMBL3622491

PubChem BioAssay actives

312 with measured affinity, of 457 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[(2S,4S)-1-[4-[2-(4-fluoro-2-methylphenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0002	uM
N-[(2S,4S)-1-[4-[2-(3,5-dimethyl-1,2-thiazol-4-yl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0003	uM
N-[(2S,4S)-1-[4-[2-(2,5-dimethyl-4-pyridinyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0004	uM
N-[(2S,4S)-1-[4-[2-(4-chloro-2-methylphenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0004	uM
N-[(2S,4S)-1-[4-[2-(2,5-dimethylphenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0005	uM
N-[(2S,4S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-1-[4-[2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl]piperidin-1-yl]sulfonylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0005	uM
N-[(2S,4S)-4-(5-fluoropyrimidin-2-yl)-1-[4-[2-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl]piperidin-1-yl]sulfonyl-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0005	uM
N-[(2S,4S)-1-[4-[2-(2-bromo-4-fluorophenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0005	uM
N-[(2S,4S)-1-[4-[2-[2-chloro-4-(trifluoromethyl)phenyl]ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0005	uM
N-[(2S,4S)-1-[4-[2-(2-chloro-4-methylsulfonylphenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0006	uM
N-[(2S,4S)-1-[4-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0007	uM
N-[(2S,4S)-1-[4-[2-(4,6-dimethyl-3-pyridinyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0007	uM
N-[(2S,4S)-1-[4-[2-[2-cyclopropyl-4-(trifluoromethyl)phenyl]ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0009	uM
(2R,3R)-1-[4-[(2-chloro-4-fluorophenyl)methoxy]phenyl]sulfonyl-N,3-dihydroxy-3-methylpiperidine-2-carboxamide	1171555: Inhibition of human ADAMTS-4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide substrate by AlphaScreen assay	ic50	0.0010	uM
N-[(2S,4S)-1-[4-[(2,4-dichlorophenyl)methoxy]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)pentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0010	uM
(2R)-N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-2-methyl-3-[4-(trifluoromethyl)phenyl]propanamide	1445577: Inhibition of human ADAMTS4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide as substrate after 3 hrs by Alphascreen assay	ic50	0.0010	uM
(2R,5R)-1-[4-[(2,4-dichlorophenyl)methoxy]phenyl]sulfonyl-N,5-dihydroxy-3,3-dimethylpiperidine-2-carboxamide	593448: Inhibition of human recombinant aggrecanase 1 after 150 mins by fluorescence plate reader	ic50	0.0011	uM
N-[(2S,4S)-1-[4-[2-(2,4-dichlorophenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0011	uM
N-[1-(cyclobutanecarbonyl)-4-[[4-[2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl]piperidin-1-yl]sulfonylmethyl]piperidin-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0012	uM
N-[4-[[4-[2-(4-chloro-2-methylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]-1-(cyclobutanecarbonyl)piperidin-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0012	uM
N-[(2S,4S)-1-[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)pentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0014	uM
N-[4-[[4-[2-(2-cyclopropyl-4-methylsulfonylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]oxan-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0014	uM
N-[(2S,4S)-1-[4-[2-(2,5-dimethyl-3-pyridinyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0019	uM
N-[1-(cyclobutanecarbonyl)-4-[[4-[2-(4-fluoro-2-methylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]piperidin-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0019	uM
(2R)-N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-2-[[4-(trifluoromethyl)phenyl]methyl]butanamide	1445577: Inhibition of human ADAMTS4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide as substrate after 3 hrs by Alphascreen assay	ic50	0.0020	uM
(2S)-2-cyclopropyl-N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-3-[4-(trifluoromethyl)phenyl]propanamide	1445577: Inhibition of human ADAMTS4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide as substrate after 3 hrs by Alphascreen assay	ic50	0.0020	uM
N-[(2S,4S)-4-(5-fluoropyrimidin-2-yl)-2-methyl-1-[4-[2-[3-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]piperidin-1-yl]sulfonylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0021	uM
N-[4-[[4-[2-(4-chloro-2-methylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]oxan-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0027	uM
N-[(2S,4S)-1-[4-[2-(2-chloro-5-fluorophenyl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0028	uM
5-chloro-N-[[(4S)-4-(1-methylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl]-1-benzofuran-2-carboxamide	1625614: Inhibition of human ADAMTS4 using 43-mer VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG as substrate measured after 3 hrs by AlphaScreen assay	ic50	0.0030	uM
(2S,3R)-2-(cyclopropylmethylamino)-N-hydroxy-N’-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-[(3-hydroxyphenyl)methyl]butanediamide	1934550: Inhibition of recombinant human ADAMTS-4	ic50	0.0030	uM
N-[(2S,4S)-1-[4-[(2,4-dichlorophenyl)methoxy]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0035	uM
N-[(2S,4S)-1-[4-[2-(2,4-dichlorophenyl)ethyl]piperazin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0038	uM
N-[[(4S)-4-(1-methylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl]-5-(trifluoromethyl)-1-benzofuran-2-carboxamide	1171555: Inhibition of human ADAMTS-4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide substrate by AlphaScreen assay	ic50	0.0040	uM
N-[[(4S)-4-(1-ethylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl]-5-(trifluoromethyl)-1-benzofuran-2-carboxamide	1625614: Inhibition of human ADAMTS4 using 43-mer VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG as substrate measured after 3 hrs by AlphaScreen assay	ic50	0.0040	uM
N-[[(4S)-4-(1,5-dimethylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl]-5-(trifluoromethyl)-1-benzofuran-2-carboxamide	1625614: Inhibition of human ADAMTS4 using 43-mer VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG as substrate measured after 3 hrs by AlphaScreen assay	ic50	0.0040	uM
(1S,2R,3R)-1-[[5-(4-chloropyrazol-1-yl)thiophen-2-yl]sulfonylamino]-2-methyl-3-phenylcyclopropane-1-carboxylic acid	593448: Inhibition of human recombinant aggrecanase 1 after 150 mins by fluorescence plate reader	ic50	0.0040	uM
N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-3-[4-(trifluoromethyl)phenyl]propanamide	1445577: Inhibition of human ADAMTS4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide as substrate after 3 hrs by Alphascreen assay	ic50	0.0040	uM
N-[1-(cyclobutanecarbonyl)-4-[[4-[2-(2-methylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]piperidin-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0041	uM
N-[(2S,4S)-1-[4-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0042	uM
N-[4-[[4-[2-(4-fluoro-2-methylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]oxan-4-yl]-N-hydroxyformamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0045	uM
N-[(2S,4S)-1-[4-[2-(2,5-dimethylpyrazol-3-yl)ethyl]piperidin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0054	uM
N-hydroxy-N-[4-[[4-[2-(2-methylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]oxan-4-yl]formamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0056	uM
N-hydroxy-N-[4-[[4-[2-(2-methyl-4-methylsulfonylphenyl)ethyl]piperidin-1-yl]sulfonylmethyl]oxan-4-yl]formamide	600949: Inhibition of ADAMTS-4 assessed as substrate cleavage after 16 hrs by fluorescence assay	ic50	0.0058	uM
N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-5-(trifluoromethyl)-1-benzofuran-2-carboxamide	1625614: Inhibition of human ADAMTS4 using 43-mer VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG as substrate measured after 3 hrs by AlphaScreen assay	ic50	0.0060	uM
5-chloro-N-[[(4S)-4-(1,5-dimethylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl]-1-benzofuran-2-carboxamide	1625614: Inhibition of human ADAMTS4 using 43-mer VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG as substrate measured after 3 hrs by AlphaScreen assay	ic50	0.0060	uM
4-[[[4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-(4-methylpiperazin-1-yl)ethylamino]-1,3,5-triazin-2-yl]amino]methyl]-N-ethyl-N-(3-methylphenyl)benzamide	1249954: Inhibition of recombinant human ADAMTS4 (213 to 575 amino acid residues) using WAAG-3R as substrate preincubated for 15 mins followed by substrate addition measured every 30 secs for 1 hr	ic50	0.0060	uM
N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-2,2-dimethyl-3-[4-(trifluoromethyl)phenyl]propanamide	1445577: Inhibition of human ADAMTS4 using VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG peptide as substrate after 3 hrs by Alphascreen assay	ic50	0.0070	uM
N-[(2S,4S)-1-[4-(4-fluorophenyl)piperazin-1-yl]sulfonyl-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide	580294: Inhibition of ADAMTS-4 assessed as substrate cleavage by measuring increase in fluorescence after 16 hrs	ic50	0.0073	uM
5-chloro-N-[[(4S)-4-(1-ethylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl]-1-benzofuran-2-carboxamide	1625614: Inhibition of human ADAMTS4 using 43-mer VQTVTWPDMELPLPRNITEGEARGSVILTVKPIFEVSPSPLKG as substrate measured after 3 hrs by AlphaScreen assay	ic50	0.0080	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Estradiol	increases expression, increases reaction	2
Tretinoin	affects cotreatment, decreases expression	2
GSK-J4	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
stachydrine	increases secretion, decreases reaction	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone	decreases reaction, increases activity, decreases activity, increases reaction	1
CGP 52608	affects binding, increases reaction	1
JTE 907	decreases reaction, increases activity, decreases activity, increases reaction	1
bisphenol S	decreases methylation	1
dulaglutide	decreases reaction, increases expression	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Amino Acids, Peptides, and Proteins	increases expression, decreases reaction	1
Carmustine	decreases expression	1
Cisplatin	affects cotreatment, affects expression	1
Curcumin	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Plant Extracts	decreases expression, affects cotreatment	1

ChEMBL screening assays

55 unique, capped per target: 54 binding, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1055719	Binding	Inhibition of aggrecanase-1	3,4-Disubstituted benzofuran P1’ MMP-13 inhibitors: optimization of selectivity and reduction of protein binding. — Bioorg Med Chem Lett
CHEMBL5579511	Toxicity	Inhibition of recombinant human full-length ADAMTS4 using 5,6 fluorescein[FAM]-Ala-Glu-Leu-Gln-Gly-Arg-Pro-Ile-Ser-Ile-Ala-Lyscarboxytetramethylrhodamine as substrate measured after 2 hrs by FRET assay	Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors. — RSC Med Chem

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D901	JJ012-TS4	Cancer cell line	Male
CVCL_U971	VA13-TS4	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00171977	PHASE4	COMPLETED	Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT00510354	PHASE4	COMPLETED	Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate
NCT00756509	PHASE4	COMPLETED	Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT02800330	PHASE4	COMPLETED	The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
NCT04825574	PHASE4	COMPLETED	Study for Patients Previously Treated in Avapritinib Clinical Trials
NCT00009906	PHASE3	TERMINATED	Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00041197	PHASE3	COMPLETED	Imatinib Mesylate in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed By Surgery
NCT00075218	PHASE3	COMPLETED	A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)
NCT00103168	PHASE3	COMPLETED	Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
NCT00293124	PHASE3	COMPLETED	Open-label Trial of GlivecWith Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
NCT00324987	PHASE3	TERMINATED	Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00372567	PHASE3	TERMINATED	Safety And Effectiveness Of Daily Dosing With Sunitinib Or Imatinib In Patients With Gastrointestinal Stromal Tumors
NCT00471328	PHASE3	COMPLETED	Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
NCT00685828	PHASE3	UNKNOWN	Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor
NCT00688766	PHASE3	TERMINATED	Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib
NCT00751036	PHASE3	TERMINATED	Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
NCT00785785	PHASE3	COMPLETED	A Study of Nilotinib Versus Imatinib in GIST Patients
NCT00812240	PHASE3	TERMINATED	Masitinib in First Line Treatment of Gastro-Intestinal Stromal Tumor (GIST)
NCT00956072	PHASE3	TERMINATED	Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
NCT01031628	PHASE3	TERMINATED	Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
NCT01151852	PHASE3	COMPLETED	Rechallenge of Imatinib in GIST Having no Effective Treatment: RIGHT
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01271712	PHASE3	COMPLETED	Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
NCT01289028	PHASE3	COMPLETED	Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib.
NCT01462994	PHASE3	COMPLETED	Detection of CF-DNA in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT01694277	PHASE3	COMPLETED	Masitinib in Patients With Gastrointestinal Stromal Tumour After Progression With Imatinib
NCT02260505	PHASE3	COMPLETED	Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)
NCT02576080	PHASE3	UNKNOWN	Efficacy of Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index
NCT02866045	PHASE3	UNKNOWN	EUS-FNB vs. Single-incision Needle-knife (SINK) Biopsy for Gastrointestinal SELs
NCT03353753	PHASE3	COMPLETED	Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
NCT03426722	PHASE3	COMPLETED	L-carnitine vs Placebo for the Treatment of Muscle Cramps After Imatinib in Gastrointestinal Stromal Tumors
NCT03465722	PHASE3	COMPLETED	(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST
NCT03673501	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib
NCT04409223	PHASE3	TERMINATED	Efficacy and Safety of Famitinib Versus Sunitinib in the Treatment of Advanced Gastrointestinal Stromal Tumour Patients After Failure of Imatinib
NCT05208047	PHASE3	ACTIVE_NOT_RECRUITING	(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
NCT05734105	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib
NCT06640361	PHASE3	RECRUITING	A Study of Olverembatinib in SDH-deficient GIST.
NCT07585266	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
NCT00003939	PHASE2	COMPLETED	Ecteinascidin 743 in Treating Patients With Advanced Soft Tissue Sarcoma