MMP12

Summary

MMP12 (matrix metallopeptidase 12, HGNC:7158) is a protein-coding gene on chromosome 11q22.2, encoding Macrophage metalloelastase (P39900). May be involved in tissue injury and remodeling.

This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease degrades soluble and insoluble elastin. This gene may play a role in aneurysm formation and mutations in this gene are associated with lung function and chronic obstructive pulmonary disease (COPD). This gene is part of a cluster of MMP genes on chromosome 11.

Source: NCBI Gene 4321 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 39 total
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002426

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7158
Approved symbol	MMP12
Name	matrix metallopeptidase 12
Location	11q22.2
Locus type	gene with protein product
Status	Approved
Aliases	HME
Ensembl gene	ENSG00000262406
Ensembl biotype	protein_coding
OMIM	601046
Entrez	4321

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000571244

RefSeq mRNA: 1 — MANE Select: NM_002426 NM_002426

CCDS: CCDS73375

Canonical transcript exons

ENST00000571244 — 10 exons

Exon	Start	End
ENSE00002632018	102865776	102865935
ENSE00002648271	102867908	102868069
ENSE00002651208	102867270	102867393
ENSE00002656522	102872865	102873112
ENSE00002657493	102871594	102871719
ENSE00002662753	102866315	102866448
ENSE00002665359	102862736	102863200
ENSE00002674514	102871804	102871952
ENSE00002679936	102864146	102864252
ENSE00002680179	102874836	102874982

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 96.81.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6912 / max 681.2844, expressed in 226 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122029	3.6912	226

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	96.81	gold quality
ileal mucosa	UBERON:0000331	94.91	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.32	gold quality
decidua	UBERON:0002450	92.20	gold quality
cartilage tissue	UBERON:0002418	92.13	gold quality
vermiform appendix	UBERON:0001154	91.98	gold quality
amniotic fluid	UBERON:0000173	89.37	gold quality
colonic mucosa	UBERON:0000317	87.60	gold quality
rectum	UBERON:0001052	85.75	gold quality
caecum	UBERON:0001153	82.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.74	gold quality
epithelium of nasopharynx	UBERON:0001951	79.37	gold quality
palpebral conjunctiva	UBERON:0001812	76.56	gold quality
placenta	UBERON:0001987	76.10	gold quality
gingiva	UBERON:0001828	74.23	gold quality
gingival epithelium	UBERON:0001949	74.10	gold quality
lymph node	UBERON:0000029	72.08	gold quality
colonic epithelium	UBERON:0000397	70.51	gold quality
stromal cell of endometrium	CL:0002255	68.42	gold quality
tonsil	UBERON:0002372	66.86	gold quality
duodenum	UBERON:0002114	64.28	gold quality
pancreatic ductal cell	CL:0002079	64.11	gold quality
gall bladder	UBERON:0002110	63.42	gold quality
large intestine	UBERON:0000059	62.22	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.81	gold quality
calcaneal tendon	UBERON:0003701	61.81	gold quality
intestine	UBERON:0000160	61.75	gold quality
mucosa of transverse colon	UBERON:0004991	61.36	gold quality
epithelial cell of pancreas	CL:0000083	61.05	silver quality
colon	UBERON:0001155	61.04	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, EGR1, FOSL1, JUN, JUND, MAFB, PPARA, PPARG, RELA, SPIC, THRA, THRB, YBX1

miRNA regulators (miRDB)

27 targeting MMP12, 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-3924	100.00	72.09	2394
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6715B-3P	98.80	68.07	1204
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-633	98.35	69.45	1167
HSA-MIR-3977	98.00	68.17	1500
HSA-MIR-6807-5P	97.51	64.25	1046
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-4633-5P	96.17	66.36	501

Literature-anchored findings (GeneRIF, showing 40)

• substrate specificity based on x ray crystallography (PMID:11575928)
• crystal structure in complex with hydroxamic acid inhibitor (PMID:11575929)
• These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms. (PMID:11875051)
• The presence of MMP-12 has been demonstrated in multiple sclerosis (MS) lesions, particularly in foamy macrophages in actively demyelinating lesions, suggesting a role for MMP-12 during demyelination in MS. (PMID:12742660)
• Migration of monocytes/macrophages in vitro and in vivo is accompanied by MMP12-dependent tunnel formation and by neovascularization. (PMID:12858542)
• MMP-12 is expressed in and secreted by human bronchial epithelial cells (PMID:15474460)
• abnormal production of tropoelastin and fibrillin by heat in human skin and that their degradation by various MMP, such as MMP-12, may contribute to the accumulation of elastotic material in photoaged skin. (PMID:15654955)
• MMP-12 might be not only a prognostic marker, but also a valuable therapeutic target. (PMID:15709175)
• Chronic obstructive pulmonary disease patients produce greater quantities of MMP-12 than controls (PMID:15723202)
• findings provide novel evidence of a direct relationship between cigarette smoke exposure and MMP-12 in human airway epithelia and suggest several targets for modulation of this potentially pathogenic pathway (PMID:15781250)
• By regulating the proliferation of corneal epithelial cells, Wnt-7a and MMP-12 appear to contribute to corneal wound healing (PMID:15802269)
• NADPH oxidase restrains the MMP-12 activity of macrophages (PMID:15983040)
• cathepsin F, matrix metalloproteinases 11 and 12 are upregulated in cervical cancer (PMID:15989693)
• Matrix metalloproteinase 12, a proteinase that plays a critical role in mouse models, was the third most highly induced gene in smokers (ninefold, p < 0.0001). (PMID:16166618)
• matrix metalloproteinase 1, 3 and 12 haplotypes may associated with development of lung cancer, particularly among never smokers and men (PMID:16311244)
• Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1beta and TNF-alpha. (PMID:16359550)
• analysis of substrate specificity of matrix metalloproteinase-12 (PMID:16481329)
• the association between the functional polymorphism of matrix metalloproteinases (MMPs) and the development of chronic obstructive pulmonary disease (COPD) (PMID:16676616)
• Protective role for stromal MMP-12 in lung tumor growth; the use of the human/mouse protein chips allows us to distinguish tumor and host-derived proteases (PMID:16912171)
• A new factor, MMP-12, regulates glioma invasiveness through interaction with tenascin-C. (PMID:17178873)
• NMR structure of matrix metalloproteinase 12 (PMID:17300109)
• High expression of MMP-12 in squamous laryngeal carcinoma was related to significant hyperplasia. (PMID:17357518)
• MMP-12 is an important oncogene in high-stage and high-grade endometrial adenocarcinoma. (PMID:17574772)
• Reliable and reproducible estimates of k(cat)and K(m) from only two or three progress curves were obtained using MMP12. (PMID:17706587)
• Results describe copy number aberrations in the SDHD and MMP12 genes in an affected Solar Keratosis and control cohort. (PMID:17727250)
• Inhibitor-binding-induced perturbations of the NMR spectra of MMP-1 and MMP-3 map to similar locations across MMP-12 and encompass the internal conformational adjustments (PMID:17997411)
• Smoking and disease itself may stimulate MMP-12 expression in airway compartments (sputum and bronchoalveolar lavage)from chronic obstructive pulmonary disease patients. (PMID:18001475)
• results indicate that resident alveolar macrophages and recruited neutrophils do not play a role in the delayed macrophage recruitment induced by rhMMP-12 (PMID:18001704)
• 357Asn/Ser polymorphism not related to generalized aggressive periodontitis (PMID:18052707)
• data suggest that MMP-2 -735C/T, MMP-9 -1562C/T and MMP-12 357Asn/Ser polymorphisms are not associated with susceptibility to severe CP in Turkish population. T allele of MMP-9 -1562 gene might be associated with decreased susceptibility to severe CP. (PMID:18155181)
• Alveolar macrophage matrix metalloproteinase 1 and 12 may have a role in the lung structural changes leading to the development of emphysema. (PMID:18259971)
• potential role for MMP12 -82 A/G and MMP13 -77 A/G combined polymorphisms in superficial endometriosis. As no association was found with deep infiltrating endometriosis, these polymorphisms might protect from a more in-depth penetration of tissues. (PMID:18308831)
• Bone Marrow Stromal (BMS) cells induce MMP-12 expression in prostate cancer cells, which results in invasive cells capable of degradation of type I collagen. (PMID:18324629)
• The amino acid preferences of the different subsites on the catalytic domain of MMP-12 were analyzed. (PMID:18334288)
• we conclude that one mechanism, by which MMP-12 induces IL-8/CXCL8 release from the alveolar epithelium, is the EGFR/ERK1/2/activating protein-1 pathway. (PMID:18390828)
• The expression of HME gene in gastric cancers may be related with lower possibility of metastasis and predict a better prognosis. (PMID:18396640)
• MMP-12 may be critical to the initiation and progression of atherosclerosis via degradation of the elastic layers and/or basement membrane. (PMID:18403602)
• NMR-derived structure of catalytic domain of MMP12 is complex with N-(dibenzo[b,d] thiophene-3-sulfonyl valine. (PMID:18425585)
• MMP-12 catalytic domain recognizes triple helical peptide models of collagen V with exosites and high activity (PMID:18539597)
• MMP-12 truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists (PMID:18660381)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	mmp23bb	ENSDARG00000009825
danio_rerio	mmp25b	ENSDARG00000010556
danio_rerio	hpxa	ENSDARG00000012609
danio_rerio	mmp30	ENSDARG00000045887
danio_rerio	mmp25a	ENSDARG00000077290
danio_rerio	mmp13b	ENSDARG00000100794
mus_musculus	Mmp12	ENSMUSG00000049723
rattus_norvegicus	Mmp12	ENSRNOG00000030187
drosophila_melanogaster	Mmp1	FBGN0035049
caenorhabditis_elegans		WBGENE00006987
caenorhabditis_elegans		WBGENE00010524
caenorhabditis_elegans		WBGENE00012185
caenorhabditis_elegans		WBGENE00012364
caenorhabditis_elegans		WBGENE00016283
caenorhabditis_elegans		WBGENE00020646
caenorhabditis_elegans		WBGENE00194737

Paralogs (23): MMP25 (ENSG00000008516), MMP2 (ENSG00000087245), MMP11 (ENSG00000099953), MMP9 (ENSG00000100985), MMP15 (ENSG00000102996), HPX (ENSG00000110169), MMP8 (ENSG00000118113), MMP19 (ENSG00000123342), MMP24 (ENSG00000125966), MMP7 (ENSG00000137673), MMP20 (ENSG00000137674), MMP27 (ENSG00000137675), MMP13 (ENSG00000137745), MMP3 (ENSG00000149968), MMP21 (ENSG00000154485), MMP16 (ENSG00000156103), MMP14 (ENSG00000157227), MMP10 (ENSG00000166670), MMP26 (ENSG00000167346), MMP23B (ENSG00000189409), MMP1 (ENSG00000196611), MMP17 (ENSG00000198598), MMP28 (ENSG00000271447)

Protein

Protein identifiers

Macrophage metalloelastase — P39900 (reviewed: P39900)

Alternative names: Macrophage elastase, Matrix metalloproteinase-12

All UniProt accessions (1): P39900

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1’ site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Found in alveolar macrophages but not in peripheral blood monocytes.

Cofactor. Binds 4 Ca(2+) ions per subunit. Binds 2 Zn(2+) ions per subunit.

Domain organisation. 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 exposure to bacterial lipopolysaccharides (LPS). Inhibited by dexamethasone.

Similarity. Belongs to the peptidase M10A family.

RefSeq proteins (1): NP_002417* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000585	Hemopexin-like_dom	Domain
IPR001818	Pept_M10_metallopeptidase	Domain
IPR002477	Peptidoglycan-bd-like	Domain
IPR006026	Peptidase_Metallo	Domain
IPR018486	Hemopexin_CS	Conserved_site
IPR018487	Hemopexin-like_repeat	Repeat
IPR021158	Pept_M10A_Zn_BS	Binding_site
IPR021190	Pept_M10A	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR033739	M10A_MMP	Domain
IPR036365	PGBD-like_sf	Homologous_superfamily
IPR036375	Hemopexin-like_dom_sf	Homologous_superfamily

Pfam: PF00045, PF00413, PF01471

Enzyme classification (BRENDA):

• EC 3.4.24.65 — macrophage elastase (BRENDA: 4 organisms, 95 substrates, 46 inhibitors, 48 Km, 48 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
FELN-100	0.001–0.0047	16
MCA-PRO-LEU-GLY-LEU-DPA-ALA-ARG-NH2	0.113–0.241	16
2-AMINOBENZOYL-PLALWRSQ-2-(2,4-DINITROPHENYL)AMI	0.0202–0.0249	2
2-AMINOBENZOYL-PLGLEEA-2-(2,4-DINITROPHENYL)AMIN	0.0047–0.0091	2
2-AMINOBENZOYL-RPLALEESQ-2-(2,4-DINITROPHENYL)AM	0.0075–0.029	2
2-AMINOBENZOYL-RPLALWEEQ-2-(2,4-DINITROPHENYL)AM	0.0123–0.0146	2
2-AMINOBENZOYL-RPLALWESQ-2-(2,4-DINITROPHENYL)AM	0.0068–0.0138	2
2-AMINOBENZOYL-RPLALWRSQ-2-(2,4-DINITROPHENYL)AM	0.0144–0.0156	2
2-AMINOBENZOYL-RPLELWRSQ-2-(2,4-DINITROPHENYL)AM	0.0088–0.0093	2
2-AMINOBENZOYL-RPLGLEEA-2-(2,4-DINITROPHENYL)AMI	0.0103–0.0197	2

UniProt features (88 total): strand 33, binding site 25, turn 9, helix 7, repeat 4, glycosylation site 2, sequence variant 2, signal peptide 1, propeptide 1, chain 1, disulfide bond 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

86 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
1Y93	X-RAY DIFFRACTION	1.03
1JK3	X-RAY DIFFRACTION	1.09
3F17	X-RAY DIFFRACTION	1.1
3F18	X-RAY DIFFRACTION	1.13
3F19	X-RAY DIFFRACTION	1.13
2OXW	X-RAY DIFFRACTION	1.15
4GQL	X-RAY DIFFRACTION	1.15
3F16	X-RAY DIFFRACTION	1.16
5D2B	X-RAY DIFFRACTION	1.2
6EKN	X-RAY DIFFRACTION	1.2
2OXU	X-RAY DIFFRACTION	1.24
7OVY	X-RAY DIFFRACTION	1.24
3F1A	X-RAY DIFFRACTION	1.25
4GR8	X-RAY DIFFRACTION	1.3
3UVC	X-RAY DIFFRACTION	1.3
5CXA	X-RAY DIFFRACTION	1.3
6EOX	X-RAY DIFFRACTION	1.3
5CZM	X-RAY DIFFRACTION	1.3
3LJG	X-RAY DIFFRACTION	1.31
5D3C	X-RAY DIFFRACTION	1.31
2HU6	X-RAY DIFFRACTION	1.32
1RMZ	X-RAY DIFFRACTION	1.34
5LAB	X-RAY DIFFRACTION	1.34
4H30	X-RAY DIFFRACTION	1.43
6ELA	X-RAY DIFFRACTION	1.49
4GR3	X-RAY DIFFRACTION	1.49
4GR0	X-RAY DIFFRACTION	1.5
4H76	X-RAY DIFFRACTION	1.5
3N2V	X-RAY DIFFRACTION	1.55
3TS4	X-RAY DIFFRACTION	1.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P39900-F1	87.35	0.69

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): 219

Ligand- & substrate-binding residues (25): 124; 158; 168; 170; 175; 176; 178; 180; 183; 190; 192; 194 …

Disulfide bonds (1): 282–470

Glycosylation sites (2): 20, 285

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 310 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, MODULE_172, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, chr11q22, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), proteolysis (GO:0006508), protein import into nucleus (GO:0006606), extracellular matrix disassembly (GO:0022617), extracellular matrix organization (GO:0030198), collagen catabolic process (GO:0030574), positive regulation of interferon-alpha production (GO:0032727), wound healing, spreading of epidermal cells (GO:0035313), positive regulation of transcription by RNA polymerase II (GO:0045944), lung alveolus development (GO:0048286), regulation of defense response to virus by host (GO:0050691), positive regulation of epithelial cell proliferation involved in wound healing (GO:0060054), elastin catabolic process (GO:0060309), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), positive regulation of type I interferon-mediated signaling pathway (GO:0060340), bronchiole development (GO:0060435), cellular response to virus (GO:0098586), response to amyloid-beta (GO:1904645), negative regulation of endothelial cell-matrix adhesion (GO:1904905), positive regulation of gene expression (GO:0010628)

GO Molecular Function (12): core promoter sequence-specific DNA binding (GO:0001046), endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), collagen binding (GO:0005518), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Degradation of the extracellular matrix	1
Extracellular matrix organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
lung development	2
type I interferon-mediated signaling pathway	2
regulation of type I interferon-mediated signaling pathway	2
peptidase activity	2
endopeptidase activity	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
protein metabolic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cellular component disassembly	1
extracellular matrix organization	1
extracellular structure organization	1
external encapsulating structure organization	1
catabolic process	1
collagen metabolic process	1
positive regulation of type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
wound healing, spreading of cells	1
positive regulation of DNA-templated transcription	1
anatomical structure development	1
regulation of defense response to virus	1
wound healing	1
positive regulation of epithelial cell proliferation	1
glycoprotein catabolic process	1
elastin metabolic process	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
positive regulation of cytokine-mediated signaling pathway	1
positive regulation of innate immune response	1
respiratory tube development	1
response to virus	1
response to nitrogen compound	1
response to oxygen-containing compound	1
negative regulation of cell-matrix adhesion	1

Protein interactions and networks

STRING

2106 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMP12	ELN	P15502	943
MMP12	TIMP1	P01033	907
MMP12	ELANE	P08246	740
MMP12	CCL2	P13500	730
MMP12	IL1B	P01584	729
MMP12	TGFB1	P01137	724
MMP12	IL6	P05231	718
MMP12	CTSS	P25774	714
MMP12	TNF	P01375	711
MMP12	FN1	P02751	705
MMP12	ITGB6	P18564	701
MMP12	IL13	P35225	683
MMP12	TIMP2	P16035	681
MMP12	CD68	P34810	647
MMP12	TIMP4	Q99727	641

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ELN	MMP12	psi-mi:“MI:0194”(cleavage reaction)	0.440
MMP12	HNRNPC	psi-mi:“MI:0915”(physical association)	0.400
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): MMP12 (Proximity Label-MS), MMP12 (Affinity Capture-MS), MMP16 (Negative Genetic), MMP12 (Negative Genetic), MMP12 (Proximity Label-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A5HMM7, B2KNH9, B5LYJ9, C0HJM8, C0HLU1, C0HM45, D4AEP7, O13065, O23547, O60882, O70138, O81320, O88766, P02874, P03956, P08253, P08688, P09353, P0DQV9, P13943, P18670, P19667, P21692, P22894, P28053, P30617, P33434, P33436, P39900, P42664, P49329, P79227, P81180, P83886, P86626, Q03380, Q39487, Q43418, Q6F495, Q6Y4Q5

Diamond homologs: A4KX75, D0EM77, G5EBU3, O04529, O18733, O18767, O18927, O23507, O55123, O55761, O60882, O62806, O77656, P03956, P03957, P07152, P08253, P08254, P09237, P09238, P13943, P14780, P21692, P22757, P23097, P28862, P28863, P29136, P33434, P33435, P33436, P34960, P39900, P41245, P41246, P45452, P50280, P50281, P50282, P50757

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MMP12	“down-regulates quantity by destabilization”	F12	cleavage
MMP12	“down-regulates quantity by destabilization”	FGA	cleavage
MMP12	up-regulates	ECM_disassembly
MMP12	down-regulates	ECM

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

955 predictions. Top by Δscore:

Variant	Effect	Δscore
11:102864141:CTT:C	donor_loss	1.0000
11:102864142:TTAC:T	donor_loss	1.0000
11:102864143:TA:T	donor_loss	1.0000
11:102864144:A:AC	donor_gain	1.0000
11:102864144:ACTG:A	donor_loss	1.0000
11:102864145:C:CT	donor_gain	1.0000
11:102864145:CT:C	donor_gain	1.0000
11:102864145:CTG:C	donor_gain	1.0000
11:102864145:CTGT:C	donor_gain	1.0000
11:102864145:CTGTT:C	donor_gain	1.0000
11:102864248:CATAC:C	acceptor_gain	1.0000
11:102864250:TAC:T	acceptor_gain	1.0000
11:102864252:CCTG:C	acceptor_loss	1.0000
11:102864253:CTGA:C	acceptor_loss	1.0000
11:102866310:ATTAC:A	donor_loss	1.0000
11:102866311:TTA:T	donor_loss	1.0000
11:102866312:TACC:T	donor_loss	1.0000
11:102866313:A:AG	donor_loss	1.0000
11:102866314:C:A	donor_loss	1.0000
11:102866386:C:CT	acceptor_gain	1.0000
11:102867264:TCCTA:T	donor_loss	1.0000
11:102867265:CCTAC:C	donor_loss	1.0000
11:102867266:CTA:C	donor_loss	1.0000
11:102867267:TA:T	donor_loss	1.0000
11:102867268:A:AC	donor_gain	1.0000
11:102867269:C:CC	donor_gain	1.0000
11:102867269:C:T	donor_loss	1.0000
11:102867269:CCTGT:C	donor_gain	1.0000
11:102867389:GTCTC:G	acceptor_gain	1.0000
11:102867391:CTC:C	acceptor_gain	1.0000

AlphaMissense

3154 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:102865837:C:G	A382P	0.990
11:102871814:A:C	F163L	0.988
11:102871814:A:T	F163L	0.988
11:102871816:A:G	F163L	0.988
11:102871697:A:C	F174L	0.986
11:102871697:A:T	F174L	0.986
11:102871699:A:G	F174L	0.986
11:102866360:C:G	A334P	0.983
11:102871882:A:G	W141R	0.980
11:102871882:A:T	W141R	0.980
11:102864167:C:G	A431P	0.978
11:102867313:C:G	A290P	0.977
11:102865834:C:G	A383P	0.975
11:102865833:G:T	A383D	0.974
11:102871856:G:C	F149L	0.974
11:102871856:G:T	F149L	0.974
11:102871858:A:G	F149L	0.974
11:102868049:C:G	A216P	0.971
11:102873011:C:A	Q68H	0.971
11:102873011:C:G	Q68H	0.971
11:102868011:A:C	H228Q	0.970
11:102868011:A:T	H228Q	0.970
11:102871664:A:C	F185L	0.970
11:102871664:A:T	F185L	0.970
11:102871666:A:G	F185L	0.970
11:102867984:G:C	F237L	0.968
11:102867984:G:T	F237L	0.968
11:102867986:A:G	F237L	0.968
11:102871698:A:C	F174C	0.968
11:102867995:C:G	A234P	0.967

dbSNP variants (sampled 300 via entrez): RS1000028164 (11:102864555 G>A,T), RS1000416970 (11:102871752 A>G,T), RS1000927175 (11:102871364 A>G), RS1001679108 (11:102872568 C>G,T), RS1002113699 (11:102867619 T>C), RS1002420340 (11:102874505 T>A), RS1003627380 (11:102862368 T>C), RS1003686487 (11:102876210 T>C), RS1003687414 (11:102875800 T>A), RS1003714830 (11:102869477 G>A), RS1003788332 (11:102869110 A>G), RS1005747831 (11:102872401 C>T), RS1006003690 (11:102867225 A>T), RS1006083099 (11:102873632 C>G), RS1007604389 (11:102868967 C>T)

Disease associations

OMIM: gene MIM:601046 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001529_3	Alzheimer’s disease	1.000000e-06
GCST002350_5	Chronic obstructive pulmonary disease (severe)	3.000000e-09
GCST002525_18	Local histogram emphysema pattern	2.000000e-07
GCST002525_21	Local histogram emphysema pattern	7.000000e-09
GCST002525_4	Local histogram emphysema pattern	1.000000e-08
GCST002525_7	Local histogram emphysema pattern	3.000000e-09
GCST002665_4	Cerebrospinal fluid levels of Alzheimer’s disease-related proteins	2.000000e-44
GCST002945_19	Emphysema imaging phenotypes	5.000000e-07
GCST002945_36	Emphysema imaging phenotypes	1.000000e-07
GCST002945_43	Emphysema imaging phenotypes	4.000000e-07
GCST002945_44	Emphysema imaging phenotypes	6.000000e-06
GCST002945_45	Emphysema imaging phenotypes	7.000000e-07
GCST003262_36	Post bronchodilator FEV1	3.000000e-06
GCST003262_654	Post bronchodilator FEV1	1.000000e-06
GCST003262_775	Post bronchodilator FEV1	1.000000e-06
GCST003262_809	Post bronchodilator FEV1	1.000000e-06
GCST003264_384	Post bronchodilator FEV1/FVC ratio	6.000000e-10
GCST003264_4	Post bronchodilator FEV1/FVC ratio	5.000000e-10
GCST003264_6	Post bronchodilator FEV1/FVC ratio	8.000000e-10
GCST003264_662	Post bronchodilator FEV1/FVC ratio	8.000000e-07
GCST003265_456	Post bronchodilator FEV1/FVC ratio in COPD	4.000000e-06
GCST003265_459	Post bronchodilator FEV1/FVC ratio in COPD	4.000000e-06
GCST006039_3	Peanut allergy	3.000000e-07
GCST006585_1814	Blood protein levels	5.000000e-77
GCST009731_45	Blood protein levels in cardiovascular risk	3.000000e-171

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005850	emphysema pattern measurement
EFO:0004744	matrix metalloproteinase measurement
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0007626	emphysema imaging measurement
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0007017	peanut allergy measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4393 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 146,774 (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
CHEMBL734	ACETOHYDROXAMIC ACID	4	7,079
CHEMBL279785	MARIMASTAT	3	29,447
CHEMBL50	QUERCETIN	3	74,559
CHEMBL151	LUTEOLIN	2	23,523
CHEMBL19611	ILOMASTAT	2	12,065
CHEMBL1233524	MK-3281	1	66
CHEMBL4859268	AGG-523	1	35

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M10: Matrix metallopeptidase

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
BAY-7598	Binding	11.4	pKd
compound 20 [PMID: 22153340]	Inhibition	10.0	pIC50
ilomastat	Inhibition	9.34	pIC50
AZD6605	Inhibition	9.22	pIC50
RXP470.1	Inhibition	8.62	pKi
AZD1236	Inhibition	8.21	pIC50
compound 1 [PMID: 24900526]	Inhibition	6.54	pIC50
TP0556351	Inhibition	5.86	pIC50
compound 5 [PMID: 24900526]	Inhibition	4.89	pIC50

Binding affinities (BindingDB)

165 measured of 273 human assays (274 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-3-methyl-2-{[12-({[2-(thiophen-2-yl)ethyl]carbamoyl}amino)-8-oxatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaene-5-]sulfonamido}butanoic acid	IC50	1.1 nM
(2S)-2-({4-[4-(1-benzofuran-2-amido)phenyl]benzene}sulfonamido)-3-methylbutanoic acid	IC50	1.3 nM
(2S)-2-({12-[(cyclopentylcarbamoyl)amino]-8-oxatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaene-5-}sulfonamido)-3-methylbutanoic acid	IC50	2.1 nM
(2S)-3-methyl-2-({12-[(thiophen-3-ylcarbamoyl)amino]-8-oxatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaene-5-}sulfonamido)butanoic acid	IC50	3.3 nM
(2S)-3-methyl-2-({12-[(propoxycarbonyl)amino]-8-oxatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaene-5-}sulfonamido)butanoic acid	IC50	10 nM
(2S)-3-methyl-2-[(12-{[(2-methylpropoxy)carbonyl]amino}-8-oxatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaene-5-)sulfonamido]butanoic acid	IC50	10 nM
(2S)-2-[(12-{[(2-fluoroethoxy)carbonyl]amino}-8-oxatricyclo[7.4.0.0^{2,7}]trideca-1(9),2(7),3,5,10,12-hexaene-5-)sulfonamido]-3-methylbutanoic acid	IC50	10 nM
(4S)-5-[3-(carboxymethyl)piperidin-1-yl]-5-oxo-4-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]pentanoic acid	KI	12 nM	US-8691753
(4S)-5-[3-(carboxymethyl)anilino]-5-oxo-4-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]pentanoic acid	KI	18.1 nM	US-8691753
(4S)-5-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxo-4-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]pentanoic acid	KI	31 nM	US-8691753
(4S)-5-amino-4-[[(2S)-3-carboxy-2-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]propanoyl]amino]-5-oxopentanoic acid	KI	39 nM	US-8691753
(4S)-5-[[(2S)-1,5-diamino-1,5-dioxopentan-2-yl]amino]-5-oxo-4-[3-[3-(4-phenylphenyl)-1,2-oxazol-5-yl]propanoylamino]pentanoic acid	KI	39.3 nM	US-8691753
(4S)-5-[[(2S)-1,5-diamino-1,5-dioxopentan-2-yl]amino]-5-oxo-4-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]pentanoic acid	KI	45 nM	US-8691753
Inhibitor, 18	KI	47 nM
(4S)-5-[[(2S)-1-amino-1-oxopropan-2-yl]amino]-5-oxo-4-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]pentanoic acid	KI	49 nM	US-8691753
(3S)-4-amino-3-[[(2S)-3-carboxy-2-[3-[3-(4-phenylphenyl)-1,2-oxazol-5-yl]propanoylamino]propanoyl]amino]-4-oxobutanoic acid	KI	52 nM	US-8691753
(4S)-5-[[(2S)-1-amino-3-carboxy-1-oxopropan-2-yl]amino]-5-oxo-4-[3-[4-(4-phenylphenyl)phenyl]propanoylamino]pentanoic acid	KI	55 nM	US-8691753
5-[2-[4-[(3-methylphenyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(3-methylphenyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[3-[4-[(3-methylphenyl)methoxy]phenyl]sulfanyl-2-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[3-[4-[(3-methylphenyl)methoxy]phenyl]sulfanyl-4-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[[4-(hydroxymethyl)phenyl]methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[[2-(hydroxymethyl)phenyl]methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
[3-[[4-[[3-(2,5-dioxoimidazolidin-4-yl)-4-pyridinyl]sulfanyl]phenoxy]methyl]phenyl]methyl (2S)-2-amino-3-methylbutanoate	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[3-[4-[[4-(hydroxymethyl)phenyl]methoxy]phenyl]sulfanyl-4-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[[3-(hydroxymethyl)phenyl]methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(2-methyl-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
3-[[4-[[3-(2,5-dioxoimidazolidin-4-yl)-4-pyridinyl]sulfanyl]phenoxy]methyl]-N-methylbenzamide	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(2-methoxy-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(2-ethoxy-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(2-propan-2-yloxy-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[[4-[[3-(2,5-dioxoimidazolidin-4-yl)-4-pyridinyl]sulfanyl]phenoxy]methyl]pyridine-3-carboxamide	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[2-methyl-4-[(2-methyl-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(2-methyl-4-pyridinyl)oxymethyl]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[6-methyl-4-[4-[(2-methyl-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[3-chloro-4-[(2-methyl-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[3-fluoro-4-[(2-methyl-4-pyridinyl)methoxy]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[3-[4-[[2-(hydroxymethyl)-4-pyridinyl]methoxy]phenyl]sulfanyl-4-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(2-methyl-4-pyridinyl)methylamino]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[methyl-[(2-methyl-4-pyridinyl)methyl]amino]phenyl]sulfanyl-3-pyridinyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
4-[[4-[[3-(2,5-dioxoimidazolidin-4-yl)-4-pyridinyl]sulfanyl]phenoxy]methyl]pyridine-2-carboxamide	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[2-[4-[(3-methylphenyl)methoxy]phenyl]sulfanylphenyl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(3-methylphenyl)methoxy]phenyl]sulfanyl-1-oxidopyridin-1-ium-3-yl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[1-methyl-4-[4-[(3-methylphenyl)methoxy]phenyl]sulfanylpyrazol-5-yl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[3-methyl-5-[4-[(3-methylphenyl)methoxy]phenyl]sulfanylimidazol-4-yl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[4-[4-[(3-methylphenyl)methoxy]phenyl]sulfanyl-1,3-oxazol-5-yl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
5-[1-methyl-5-[4-[(2-methyl-4-pyridinyl)methoxy]phenyl]sulfanylimidazol-4-yl]imidazolidine-2,4-dione	IC50	55 nM	US-20250115590: MATRIX METALLOPROTEINASE (MMP) INHIBITORS AND METHODS OF USE THEREOF
Inhibitor, 17	KI	57 nM

ChEMBL bioactivities

710 potent at pChembl≥5 of 792 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.07	IC50	0.085	nM	BAY-7598
10.00	IC50	0.1	nM	CHEMBL1935285
10.00	IC50	0.1	nM	CHEMBL1935286
9.72	Ki	0.19	nM	CHEMBL507420
9.72	Ki	0.19	nM	CHEMBL5191016
9.70	IC50	0.2	nM	CHEMBL573715
9.70	IC50	0.2	nM	CHEMBL179288
9.70	IC50	0.2	nM	CHEMBL1935287
9.70	IC50	0.2	nM	CHEMBL1935288
9.62	IC50	0.24	nM	CHEMBL111856
9.62	Ki	0.24	nM	CHEMBL507420
9.59	Ki	0.26	nM	CHEMBL507420
9.59	Ki	0.26	nM	CHEMBL4581500
9.55	Ki	0.28	nM	CHEMBL2316257
9.52	Ki	0.3	nM	CHEMBL3675605
9.52	IC50	0.3	nM	CHEMBL1935304
9.43	IC50	0.368	nM	CHEMBL5288452
9.40	IC50	0.4	nM	CHEMBL561312
9.40	IC50	0.4	nM	CHEMBL1935284
9.40	IC50	0.4	nM	CHEMBL1935290
9.34	IC50	0.46	nM	ILOMASTAT
9.28	Ki	0.52	nM	ILOMASTAT
9.25	IC50	0.566	nM	CHEMBL5280430
9.21	Ki	0.61	nM	CHEMBL115727
9.15	IC50	0.7	nM	CHEMBL1935280
9.07	IC50	0.85	nM	CHEMBL573715
9.05	Ki	0.9	nM	CHEMBL4435285
9.05	IC50	0.9	nM	CHEMBL523683
9.05	IC50	0.89	nM	CHEMBL573715
9.03	IC50	0.93	nM	CHEMBL2337131
9.02	IC50	0.95	nM	CHEMBL366111
9.00	Ki	1	nM	CHEMBL2385483
9.00	Ki	1	nM	CHEMBL3133269
9.00	Ki	1	nM	CHEMBL4520279
9.00	Ki	1	nM	CHEMBL4764575
9.00	IC50	1	nM	ILOMASTAT
9.00	IC50	1	nM	CHEMBL1935291
8.98	Ki	1.05	nM	CHEMBL3675573
8.96	Ki	1.1	nM	CHEMBL4751015
8.96	IC50	1.1	nM	CHEMBL493356
8.92	Ki	1.2	nM	CHEMBL4739996
8.92	IC50	1.2	nM	CHEMBL5199189
8.92	IC50	1.2	nM	CHEMBL1935292
8.89	IC50	1.3	nM	CHEMBL5183245
8.85	IC50	1.4	nM	CHEMBL550038
8.80	IC50	1.6	nM	CHEMBL1935300
8.79	Ki	1.63	nM	CHEMBL3675563
8.77	IC50	1.7	nM	CHEMBL77163
8.77	IC50	1.698	nM	CHEMBL77163
8.74	IC50	1.8	nM	CHEMBL3958969

PubChem BioAssay actives

643 with measured affinity, of 1139 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
(2S)-2-[[8-(5-chlorofuran-2-yl)dibenzofuran-3-yl]sulfonylamino]-3-methylbutanoic acid	638695: Inhibition of human MMP-12	ic50	0.0001	uM
(2S)-3-methyl-2-[[8-(5-methylfuran-2-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0001	uM
(2R)-N-hydroxy-3-methyl-2-[(4-phenylphenyl)sulfonyl-propan-2-yloxyamino]butanamide	440420: Inhibition of autoactivated human pro-MMP12 after 4 hrs by fluorimetry	ic50	0.0002	uM
(4R)-5-amino-4-[[(2R)-2-[[(2R)-2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid	1863959: Inhibition of human MMP-12 expressed in Escherichia coli BL21(DE3) using Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 as substrate preincubated for 30 mins followed by susbstrate addition by photon-counter spectrophotometer analysis	ki	0.0002	uM
N-hydroxy-2-[2-[4-(4-methoxyphenoxy)phenyl]sulfonylphenyl]acetamide	440420: Inhibition of autoactivated human pro-MMP12 after 4 hrs by fluorimetry	ic50	0.0002	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid	349385: Inhibition of MMP12	ki	0.0002	uM
(2S)-3-methyl-2-[(8-thiophen-2-yldibenzofuran-3-yl)sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0002	uM
(2S)-3-methyl-2-[[8-(5-methylthiophen-2-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0002	uM
(4R)-5-amino-4-[[(2S)-2-[[2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid	1799769: Enzyme Assay from Article 10.1074/jbc.M112.380782: “Simple Pseudo-dipeptides with a P2’ Glutamate: A NOVEL INHIBITOR FAMILY OF MATRIX METALLOPROTEASES AND OTHER METZINCINS.”	ki	0.0002	uM
4-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]-N-hydroxyoxane-4-carboxamide	109242: Inhibition of matrix metalloprotease-12	ic50	0.0002	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid	1524641: Inhibition of human MMP12	ki	0.0003	uM
(2S)-3-methyl-2-[[8-[5-(oxolan-3-yl)-1,2,4-oxadiazol-3-yl]dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0003	uM
[(2S)-3-[[(2S)-1-[[(2S)-1-amino-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-[[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]methyl]-3-oxopropyl]-(4-bromophenyl)phosphinic acid	1524641: Inhibition of human MMP12	ki	0.0003	uM
(2S)-3-methyl-2-[[4-[5-(5-methylthiophen-2-yl)-1,2-oxazol-3-yl]phenyl]sulfonylamino]butanoic acid	1937792: Inhibition of MMP12 (unknown origin)	ic50	0.0004	uM
(2S)-2-[[8-(methoxycarbonylamino)dibenzothiophen-3-yl]sulfonylamino]-3-methylbutanoic acid	427755: Inhibition of human recombinant MMP12	ic50	0.0004	uM
(2S)-2-[[8-(furan-3-yl)dibenzofuran-3-yl]sulfonylamino]-3-methylbutanoic acid	638695: Inhibition of human MMP-12	ic50	0.0004	uM
(2S)-3-methyl-2-[[8-(1H-pyrrol-2-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0004	uM
(2R)-N’-hydroxy-N-[(2S)-3-(1H-indol-3-yl)-1-(methylamino)-1-oxopropan-2-yl]-2-(2-methylpropyl)butanediamide	1912254: Inhibition of recombinant human MMP12 using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as substrate preincubated for 15 mins followed by substrate addition by fluroscence based assay	ic50	0.0005	uM
(2S)-2-[[4-[5-(5-ethylthiophen-2-yl)-1,2-oxazol-3-yl]phenyl]sulfonylamino]-3-methylbutanoic acid	1937792: Inhibition of MMP12 (unknown origin)	ic50	0.0006	uM
(2S)-3-methyl-2-[[8-[3-(trifluoromethyl)pyrazol-1-yl]dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0007	uM
(2E)-2-[(2E,4E)-5-[3-[6-[3-[2-[2-[3-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(4-bromophenyl)-hydroxyphosphoryl]methyl]-3-[3-[4-(3-chlorophenyl)phenyl]-1,2-oxazol-5-yl]propanoyl]amino]propanoyl]amino]-4-carboxybutanoyl]amino]propoxy]ethoxy]ethoxy]propylamino]-6-oxohexyl]-1,1-dimethyl-6,8-disulfobenzo[e]indol-3-ium-2-yl]penta-2,4-dienylidene]-3-ethyl-1,1-dimethyl-8-sulfobenzo[e]indole-6-sulfonate	1524641: Inhibition of human MMP12	ki	0.0009	uM
(2S)-3-methyl-2-[[8-(thiophen-3-ylcarbamoylamino)dibenzofuran-3-yl]sulfonylamino]butanoic acid	1798893: MMP Inhibition Assay from Article 10.1021/jm900093d: “A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408).”	ic50	0.0009	uM
2-(2,5-dichlorophenyl)sulfonyl-N-hydroxy-6-phenoxy-3,4-dihydro-1H-isoquinoline-1-carboxamide	731523: Inhibition of MMP12 (unknown origin)	ic50	0.0009	uM
(3S,4R)-4-[4-[(2,4-dichlorophenyl)methoxy]phenyl]sulfonyl-N,3-dihydroxyoxane-3-carboxamide	240999: Inhibition of matrix metalloprotease 12	ic50	0.0009	uM
(6S,7R,10S)-10-N-[(2S)-5-(diaminomethylideneamino)-1-(methylamino)-1-oxopentan-2-yl]-6-N-hydroxy-7-(2-methylpropyl)-8-oxo-2-oxa-9-azabicyclo[10.2.2]hexadeca-1(14),12,15-triene-6,10-dicarboxamide	1701081: Inhibition of human recombinant MMP12 using Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 substrate by spectrophotometry	ki	0.0010	uM
[(2S)-3-[[(2S)-1-[[(2S)-1-[3-[2-[2-[3-(2,3-ditritiopropanoylamino)propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-3-oxo-2-[[3-[4-[3-(trifluoromethyl)diazirin-3-yl]phenyl]-1,2-oxazol-5-yl]methyl]propyl]-phenylphosphinic acid	1524649: Inhibition of human MMP12 by photoaffinity probe based assay	ki	0.0010	uM
(2R,3R)-1-[4-[(2-chloro-4-fluorophenyl)methoxy]phenyl]sulfonyl-N,3-dihydroxy-3-methylpiperidine-2-carboxamide	1445582: Inhibition of human MMP12 using Mca-PQGL-(3-[2, 4-dinitrophenyl]-L-2, 3-diaminopropionyl)-AR-OH as substrate after 2 to 4 hrs by fluorescence assay	ic50	0.0010	uM
(2S)-3-methyl-2-[[8-(1,3-thiazol-2-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0010	uM
(2S)-3-methyl-2-[[8-(1H-pyrazol-5-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0010	uM
(2S)-N-hydroxy-1-[2-(4-methoxyphenyl)ethylsulfonyl]pyrrolidine-2-carboxamide	748347: Inhibition of MMP12 (unknown origin)-mediated Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 by fluorimetric assay	ki	0.0010	uM
(6S,7R,10S)-6-(hydroxycarbamoyl)-7-(2-methylpropyl)-8-oxo-2-oxa-9-azabicyclo[10.2.2]hexadeca-1(14),12,15-triene-10-carboxylic acid	1701081: Inhibition of human recombinant MMP12 using Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 substrate by spectrophotometry	ki	0.0011	uM
(2S)-3-methyl-2-[[8-(2-thiophen-2-ylethylcarbamoylamino)dibenzofuran-3-yl]sulfonylamino]butanoic acid	1798893: MMP Inhibition Assay from Article 10.1021/jm900093d: “A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408).”	ic50	0.0011	uM
(2S)-2-[[(6S,7R,10S)-6-(hydroxycarbamoyl)-7-(2-methylpropyl)-8-oxo-2-oxa-9-azabicyclo[10.2.2]hexadeca-1(14),12,15-triene-10-carbonyl]amino]pentanedioic acid	1701081: Inhibition of human recombinant MMP12 using Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 substrate by spectrophotometry	ki	0.0012	uM
N-hydroxy-4-[4-[4-(4-methoxyphenyl)triazol-1-yl]phenyl]sulfonyloxane-4-carboxamide	1863880: Inhibition of MMP-12 (unknown origin)	ic50	0.0012	uM
(2S)-3-methyl-2-[[8-(5-methyl-1,3-thiazol-2-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	638695: Inhibition of human MMP-12	ic50	0.0012	uM
(3S)-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]-methylamino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-[[(2S)-4-amino-4-oxo-2-[4-[(4-phenoxyphenyl)sulfonylamino]butanoylamino]butanoyl]amino]-4-oxobutanoic acid	1912254: Inhibition of recombinant human MMP12 using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as substrate preincubated for 15 mins followed by substrate addition by fluroscence based assay	ic50	0.0013	uM
(2S)-3-methyl-2-[[8-(2-oxo-1,3-oxazolidin-3-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	427755: Inhibition of human recombinant MMP12	ic50	0.0014	uM
3-methyl-2-[[8-(2-oxo-1,3-oxazolidin-3-yl)dibenzofuran-3-yl]sulfonylamino]butanoic acid	1799769: Enzyme Assay from Article 10.1074/jbc.M112.380782: “Simple Pseudo-dipeptides with a P2’ Glutamate: A NOVEL INHIBITOR FAMILY OF MATRIX METALLOPROTEASES AND OTHER METZINCINS.”	ic50	0.0014	uM
(2S)-2-[[8-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)dibenzofuran-3-yl]sulfonylamino]-3-methylbutanoic acid	638695: Inhibition of human MMP-12	ic50	0.0016	uM
(4-benzylphenyl)methyl-[4-(4-chlorophenyl)-2-[[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]carbamoyl]butyl]phosphinic acid	109241: Inhibition of matrix metalloprotease-12	ic50	0.0017	uM
N-[[3-[3-[2-(hydroxycarbamoyl)piperidin-1-yl]sulfonylpropoxy]phenyl]methyl]-4-oxo-3H-quinazoline-2-carboxamide	1328782: Inhibition of recombinant human AMPA-activated MMP12 using Cy3-PLGLK(Cy5Q)AR-NH2 as substrate measured after 40 mins by spectrofluorimetric method	ic50	0.0018	uM
(2R)-2-[[8-(methoxycarbonylamino)dibenzothiophen-3-yl]sulfonylamino]-3-methylbutanoic acid	427755: Inhibition of human recombinant MMP12	ic50	0.0018	uM
(3S)-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-(2-amino-2-oxoethyl)pyrrolidin-1-yl]-4-methylsulfanyl-1-oxobutan-2-yl]-methylamino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-[[(2S)-4-amino-4-oxo-2-[4-[(4-phenoxyphenyl)sulfonylamino]butanoylamino]butanoyl]amino]-4-oxobutanoic acid	1912254: Inhibition of recombinant human MMP12 using MOCAc-Pro-Leu-Gly-Leu-A2pr(Dnp)-Ala-Arg-NH2 as substrate preincubated for 15 mins followed by substrate addition by fluroscence based assay	ic50	0.0019	uM
(4R)-5-amino-4-[[(2S)-4-carboxy-2-[3-[4-(4-phenylthiophen-2-yl)phenyl]propanoylamino]butanoyl]amino]-5-oxopentanoic acid	1799769: Enzyme Assay from Article 10.1074/jbc.M112.380782: “Simple Pseudo-dipeptides with a P2’ Glutamate: A NOVEL INHIBITOR FAMILY OF MATRIX METALLOPROTEASES AND OTHER METZINCINS.”	ki	0.0019	uM
(2S)-2-[[8-[5-(methoxymethyl)-1,2,4-oxadiazol-3-yl]dibenzofuran-3-yl]sulfonylamino]-3-methylbutanoic acid	638695: Inhibition of human MMP-12	ic50	0.0019	uM
(2R)-N-[(2S)-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-N’-hydroxy-2-(2-methylpropyl)butanediamide	1172327: Inhibition of human recombinant MMP12 catalytic domain Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 fluorogenic substrate	ic50	0.0020	uM
N-hydroxy-2-[(4-phenylphenyl)sulfonylamino]acetamide	748347: Inhibition of MMP12 (unknown origin)-mediated Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 by fluorimetric assay	ki	0.0020	uM
(2S)-2-[[8-(methoxycarbonylamino)dibenzofuran-3-yl]sulfonylamino]-3-methylbutanoic acid	1798893: MMP Inhibition Assay from Article 10.1021/jm900093d: “A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408).”	ic50	0.0020	uM
(2R)-N-hydroxy-1-[2-(4-phenylphenyl)ethylsulfonyl]pyrrolidine-2-carboxamide	748347: Inhibition of MMP12 (unknown origin)-mediated Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 by fluorimetric assay	ki	0.0020	uM
(5S)-5-[[4-(4-ethoxyphenoxy)piperidin-1-yl]sulfonylmethyl]-5-methylimidazolidine-2,4-dione	761928: Inhibition of MMP-12 (unknown origin) by fluorescence assay	ic50	0.0020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
Nickel	affects expression, increases expression, decreases reaction	2
Tetrachlorodibenzodioxin	increases expression, decreases reaction	2
Cyclosporine	decreases methylation, increases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	increases expression	1
acetohydroxamic acid	decreases activity, affects binding	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	affects expression, decreases reaction	1
hydroxyhydroquinone	increases expression	1
trimellitic anhydride	increases expression	1
sodium arsenite	decreases expression	1
stearic acid	increases expression	1
perfluorodecanoic acid	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases activity, increases expression	1
3’-methoxy-4’-nitroflavone	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases expression, decreases reaction, increases activity	1
pyrazolanthrone	decreases reaction, increases activity, increases expression	1
lipopolysaccharide, E coli O55-B5	affects cotreatment, increases expression, increases reaction	1
abrine	increases expression	1
fenbuconazole	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Wortmannin	decreases reaction, increases activity, increases expression	1
Arsenic Trioxide	decreases expression	1
Acrolein	increases secretion	1
Azathioprine	decreases expression	1

ChEMBL screening assays

191 unique, capped per target: 183 binding, 8 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002878	Binding	Binding affinity to MMP12 assessed as enzyme mediated cleavage of compound by measuring increase in fluorescence after 16 hrs by HPLC-MS	Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers. — J Med Chem
CHEMBL2211414	ADMET	Prodrug conversion assessed as recombinant human MMP-12 mediated compound conversion to 2-((S)-2-((S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxamido)-N-(biphenyl-4-ylsulfonyl)-4-methylpentanamido)acetic acid by HPLC analysis	Target-Activated Prodrugs (TAPs) for the Autoregulated Inhibition of MMP12. — ACS Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8KM	Abcam HCT 116 MMP12 KO	Cancer cell line	Male
CVCL_B8YY	Abcam MCF-7 MMP12 KO	Cancer cell line	Female
CVCL_B9MV	Abcam A-549 MMP12 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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