Target Information

Target General Information

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Target ID

T03500 (Former ID: TTDC00157)

Target Name

Matrix metalloproteinase-12 (MMP-12)

Synonyms

Macrophage metalloelastase; Macrophage elastase; MME; ME; HME

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Gene Name

MMP12

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Asthma [ICD-11: CA23]

Lung cancer [ICD-11: 2C25]

Renal cell carcinoma [ICD-11: 2C90]

Function

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. May be involved in tissue injury and remodeling.

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BioChemical Class

Peptidase

UniProt ID

MMP12_HUMAN

EC Number

EC 3.4.24.65

Sequence

MKFLLILLLQATASGALPLNSSTSLEKNNVLFGERYLEKFYGLEINKLPVTKMKYSGNLM
KEKIQEMQHFLGLKVTGQLDTSTLEMMHAPRCGVPDVHHFREMPGGPVWRKHYITYRINN
YTPDMNREDVDYAIRKAFQVWSNVTPLKFSKINTGMADILVVFARGAHGDFHAFDGKGGI
LAHAFGPGSGIGGDAHFDEDEFWTTHSGGTNLFLTAVHEIGHSLGLGHSSDPKAVMFPTY
KYVDINTFRLSADDIRGIQSLYGDPKENQRLPNPDNSEPALCDPNLSFDAVTTVGNKIFF
FKDRFFWLKVSERPKTSVNLISSLWPTLPSGIEAAYEIEARNQVFLFKDDKYWLISNLRP
EPNYPKSIHSFGFPNFVKKIDAAVFNPRFYRTYFFVDNQYWRYDERRQMMDPGYPKLITK
NFQGIGPKIDAVFYSKNKYYYFFQGSNQFEYDFLLQRITKTLKSNSWFGC

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T76WHR

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

FP-025

Drug Info

Phase 1

Asthma

[2]

Neovastat

Drug Info

Phase 1

Renal cell carcinoma

[3]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

AZD1236

Drug Info

Discontinued in Phase 2

Chronic obstructive pulmonary disease

[4], [5]

GM6001

Drug Info

Discontinued in Phase 2

Corneal ulcer

[6]

V85546

Drug Info

Discontinued in Phase 1

Inflammation

[7]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 38 Inhibitor drugs

FP-025

Drug Info

[1]

Neovastat

Drug Info

[8], [9], [10]

PMID29130358-Compound-Figure17(10)

Drug Info

[11]

PMID29130358-Compound-Figure17(11)

Drug Info

[11]

PMID29130358-Compound-Figure17(12)

Drug Info

[11]

AZD1236

Drug Info

[12]

GM6001

Drug Info

[13]

V85546

Drug Info

[14]

(+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid

Drug Info

[15]

2-(2-(biphenyl-4-yl)ethylsulfinyl)acetic acid

Drug Info

[15]

2-(2-(biphenyl-4-yl)ethylsulfonyl)acetic acid

Drug Info

[15]

2-(2-(biphenyl-4-yl)ethylthio)acetic acid

Drug Info

[15]

2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide

Drug Info

[16]

3-(4-(2-phenylethynyl)benzoyl)pentanoic acid

Drug Info

[13]

3-(4-Phenylethynylbenzoyl)nonanoic acid

Drug Info

[13]

3-Benzenesulfonyl-heptanoic acid hydroxyamide

Drug Info

[17]

3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide

Drug Info

[17]

4-(4-(dec-1-ynyl)phenyl)-4-oxobutanoic acid

Drug Info

[13]

5-(3'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid

Drug Info

[15]

5-(4'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid

Drug Info

[15]

5-(biphenyl-4-yl)-3-methoxypentanoic acid

Drug Info

[15]

5-(biphenyl-4-yl)-3-oxopentanoic acid

Drug Info

[15]

Acetate Ion

Drug Info

[18]

AGELADINE A

Drug Info

[19]

MMP-408

Drug Info

[20]

N-(biphenyl-4-ylsulfonyl)-D-leucine

Drug Info

[21]

N-(dibenzo[b,d]thiophen-3-ylsulfonyl)-L-valine

Drug Info

[21]

N-Hydroxy-2-(4-methoxy-benzenesulfonyl)benzamide

Drug Info

[16]

N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide

Drug Info

[16]

N-oxo-2-[(4-phenylphenyl)sulfonylamino]ethanamide

Drug Info

[21]

N-[(4-methoxyphenyl)sulfonyl]-D-alanine

Drug Info

[21]

PF-00356231

Drug Info

[22]

PMID22153340C20

Drug Info

[23]

PMID24900526C5

Drug Info

[24]

RXP-470

Drug Info

[20]

RXP470.1

Drug Info

[25]

WAY-644

Drug Info

[20]

[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid

Drug Info

[16]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Acetohydroxamic acid

Ligand Info

Structure Description

Crystal structure of the catalytic domain of human MMP12 complexed with acetohydroxamic acid at atomic resolution

PDB:1Y93

Method

X-ray diffraction

Resolution

1.03 Å

Mutation

Yes

[26]

PDB Sequence

GPVWRKHYIT

¹¹⁵

YRINNYTPDM

¹²⁵

NREDVDYAIR

¹³⁵

KAFQVWSNVT

¹⁴⁵

PLKFSKINTG

¹⁵⁵

MADILVVFAR

¹⁶⁵

GAHGDDHAFD

¹⁷⁵

GKGGILAHAF

¹⁸⁵

GPGSGIGGDA

¹⁹⁵

HFDEDEFWTT

²⁰⁵

HSGGTNLFLT

²¹⁵

AVHEIGHSLG

²²⁵

LGHSSDPKAV

²³⁵

MFPTYKYVDI

²⁴⁵

NTFRLSADDI

²⁵⁵

RGIQSLYG

Residue

Distance (Å)

ILE180

2.578

LEU181

4.573

ALA182

1.835

HIS183

2.400

ALA184

4.212

Residue

Distance (Å)

HIS218

2.195

GLU219

2.343

HIS222

2.503

HIS228

2.461

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Batimastat

Ligand Info

Structure Description

Crystal structure of human MMP-12 (Macrophage Elastase) at true atomic resolution

PDB:1JK3

Method

X-ray diffraction

Resolution

1.09 Å

Mutation

Yes

[27]

PDB Sequence

GPVWRKHYIT

¹¹⁵

YRINNYTPDM

¹²⁵

NREDVDYAIR

¹³⁵

KAFQVWSNVT

¹⁴⁵

PLKFSKINTG

¹⁵⁵

MADILVVFAR

¹⁶⁵

GAHGDFHAFD

¹⁷⁵

GKGGILAHAF

¹⁸⁵

GPGSGIGGDA

¹⁹⁵

HFDEDEFWTT

²⁰⁵

HSGGTNLFLT

²¹⁵

AVHAIGHSLG

²²⁵

LGHSSDPKAV

²³⁵

MFPTYKYVDI

²⁴⁵

NTFRLSADDI

²⁵⁵

RGIQSLYG

Residue

Distance (Å)

GLY178

4.983

GLY179

2.697

ILE180

3.544

LEU181

2.812

ALA182

2.876

HIS183

4.032

ALA184

4.607

THR215

3.962

Residue

Distance (Å)

HIS218

3.144

HIS222

2.912

HIS228

2.900

PHE237

3.643

PRO238

2.883

THR239

3.662

TYR240

2.902

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.85E-01	Radiality	1.31E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	3.20E+01	Topological coefficient	1.00E+00	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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NetPath Pathway

[+] 2 NetPath Pathways

IL1 Signaling Pathway

IL5 Signaling Pathway

PID Pathway

[+] 1 PID Pathways

Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling

Reactome

[+] 2 Reactome Pathways

Collagen degradation

Degradation of the extracellular matrix

WikiPathways

[+] 3 WikiPathways

TGF beta Signaling Pathway

Degradation of collagen

Matrix Metalloproteinases

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies. Expert Rev Proteomics. 2015;12(5):445-7.

REF 2

ClinicalTrials.gov (NCT02238834) Phase 1 Safety, Tolerability and Pharmacokinetics (PK) Study of FP-025 in Healthy Volunteers

REF 3

Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.

REF 4

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7844).

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026714)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001387)

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020392)

REF 8

Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.

REF 9

Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma. J Microbiol. 2005 Feb;43(1):11-6.

REF 10

The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. Int J Oncol. 2002 Feb;20(2):299-303.

REF 11

Gelatinase inhibitors: a patent review (2011-2017).Expert Opin Ther Pat. 2018 Jan;28(1):31-46.

REF 12

Clinical pipeline report, company report or official report of AstraZeneca (2009).

REF 13

Selective inhibition of matrix metalloproteinase isozymes and in vivo protection against emphysema by substituted gamma-keto carboxylic acids. J Med Chem. 2006 Jan 26;49(2):456-8.

REF 14

Clinical pipeline report, company report or official report of Vernalis.

REF 15

The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3.

REF 16

Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhib... J Med Chem. 2009 Oct 22;52(20):6347-61.

REF 17

Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents. J Med Chem. 2000 Jun 15;43(12):2324-31.

REF 18

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 19

Synthesis of novel ageladine A analogs showing more potent matrix metalloproteinase (MMP)-12 inhibitory activity than the natural product. Bioorg Med Chem Lett. 2009 Sep 15;19(18):5461-3.

REF 20

REF 21

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 22

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 23

Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD). Bioorg Med Chem Lett. 2012 Jan 1;22(1):138-43.

REF 24

Target-Activated Prodrugs (TAPs) for the Autoregulated Inhibition of MMP12. ACS Med Chem Lett. 2012 Jul 14;3(8):653-7.

REF 25

Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies. J Med Chem. 2013 Feb 14;56(3):1149-59.

REF 26

Conformational variability of matrix metalloproteinases: beyond a single 3D structure. Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5334-9.

REF 27

Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure. J Mol Biol. 2001 Sep 28;312(4):731-42.

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