Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXZ0KQ)

• DTT Name: Matrix metalloproteinase-12 (MMP-12)
• Synonyms: Macrophage metalloelastase; Macrophage elastase; MME; ME; HME
• Gene Name: MMP12
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Asthma [ICD-11: CA23]
  Lung cancer [ICD-11: 2C25]
  Renal cell carcinoma [ICD-11: 2C90]
• BioChemical Class: Peptidase
• UniProt ID: MMP12_HUMAN
• TTD ID: T03500
• EC Number: EC 3.4.24.65
• Sequence:
  MKFLLILLLQATASGALPLNSSTSLEKNNVLFGERYLEKFYGLEINKLPVTKMKYSGNLM
  KEKIQEMQHFLGLKVTGQLDTSTLEMMHAPRCGVPDVHHFREMPGGPVWRKHYITYRINN
  YTPDMNREDVDYAIRKAFQVWSNVTPLKFSKINTGMADILVVFARGAHGDFHAFDGKGGI
  LAHAFGPGSGIGGDAHFDEDEFWTTHSGGTNLFLTAVHEIGHSLGLGHSSDPKAVMFPTY
  KYVDINTFRLSADDIRGIQSLYGDPKENQRLPNPDNSEPALCDPNLSFDAVTTVGNKIFF
  FKDRFFWLKVSERPKTSVNLISSLWPTLPSGIEAAYEIEARNQVFLFKDDKYWLISNLRP
  EPNYPKSIHSFGFPNFVKKIDAAVFNPRFYRTYFFVDNQYWRYDERRQMMDPGYPKLITK
  NFQGIGPKIDAVFYSKNKYYYFFQGSNQFEYDFLLQRITKTLKSNSWFGC
• 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.
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FP-025	DMH1NXO	Asthma	CA23	Phase 1	[1]
Neovastat	DMXTYWJ	Non-small-cell lung cancer	2C25.Y	Phase 1	[2], [3], [4]

3 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID29130358-Compound-Figure17(10)	DMVA15O	N. A.	N. A.	Patented	[5]
PMID29130358-Compound-Figure17(11)	DMSZA9L	N. A.	N. A.	Patented	[5]
PMID29130358-Compound-Figure17(12)	DMML4PA	N. A.	N. A.	Patented	[5]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD1236	DML3RSF	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[6]
GM6001	DM7V9CT	Corneal ulcer	9A76	Discontinued in Phase 2	[7]
V85546	DMLFMSY	Inflammation	1A00-CA43.1	Discontinued in Phase 1	[8]

34 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid	DMSN7GJ	Discovery agent	N.A.	Investigative	[9]
2-(2-(biphenyl-4-yl)ethylsulfinyl)acetic acid	DMDR50V	Discovery agent	N.A.	Investigative	[9]
2-(2-(biphenyl-4-yl)ethylsulfonyl)acetic acid	DM95B4J	Discovery agent	N.A.	Investigative	[9]
2-(2-(biphenyl-4-yl)ethylthio)acetic acid	DMBZIUC	Discovery agent	N.A.	Investigative	[9]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide	DMCNV5J	Discovery agent	N.A.	Investigative	[10]
3-(4-(2-phenylethynyl)benzoyl)pentanoic acid	DMQDPHT	Discovery agent	N.A.	Investigative	[7]
3-(4-Phenylethynylbenzoyl)nonanoic acid	DMXL0J5	Discovery agent	N.A.	Investigative	[7]
3-Benzenesulfonyl-heptanoic acid hydroxyamide	DM7XDCF	Discovery agent	N.A.	Investigative	[11]
3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide	DMJSOTE	Discovery agent	N.A.	Investigative	[11]
4-(4-(dec-1-ynyl)phenyl)-4-oxobutanoic acid	DM6KIG0	Discovery agent	N.A.	Investigative	[7]
5-(3'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid	DMPC9DV	Discovery agent	N.A.	Investigative	[9]
5-(4'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid	DMTDNX3	Discovery agent	N.A.	Investigative	[9]
5-(biphenyl-4-yl)-3-methoxypentanoic acid	DMJAG7M	Discovery agent	N.A.	Investigative	[9]
5-(biphenyl-4-yl)-3-oxopentanoic acid	DMQKU9H	Discovery agent	N.A.	Investigative	[9]
Acetate Ion	DMD08RH	Discovery agent	N.A.	Investigative	[12]
AGELADINE A	DMOJ3CW	Discovery agent	N.A.	Investigative	[13]
CP-271485	DMGN38F	Discovery agent	N.A.	Investigative	[12]
MMP-408	DMVCNBH	Chronic obstructive pulmonary disease	CA22	Investigative	[14]
N-(biphenyl-4-ylsulfonyl)-D-leucine	DMHPITZ	Discovery agent	N.A.	Investigative	[15]
N-(dibenzo[b,d]thiophen-3-ylsulfonyl)-L-valine	DMI245K	Discovery agent	N.A.	Investigative	[15]
N-Hydroxy-2-(4-methoxy-benzenesulfonyl)benzamide	DM56P1I	Discovery agent	N.A.	Investigative	[10]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide	DM4VADN	Discovery agent	N.A.	Investigative	[10]
N-oxo-2-(phenylsulfonylamino)ethanamide	DMQ84J7	Discovery agent	N.A.	Investigative	[15]
N-oxo-2-[(4-phenylphenyl)sulfonylamino]ethanamide	DMHTI5X	Discovery agent	N.A.	Investigative	[15]
N-[(4-methoxyphenyl)sulfonyl]-D-alanine	DMVOJFW	Discovery agent	N.A.	Investigative	[15]
PF-00356231	DMV43NF	Discovery agent	N.A.	Investigative	[16]
PMID22153340C20	DMTGVSU	Discovery agent	N.A.	Investigative	[17]
PMID24900526C1	DMEWVG8	Discovery agent	N.A.	Investigative	[18]
PMID24900526C5	DMKTBCM	Discovery agent	N.A.	Investigative	[18]
PUP-1	DMCWT4L	Chronic obstructive pulmonary disease	CA22	Investigative	[14]
RXP-470	DM5GIUY	Arteriosclerosis	BD40	Investigative	[14]
RXP470.1	DMB7EGU	Discovery agent	N.A.	Investigative	[19]
WAY-644	DMNCZEQ	Aortic aneurysm	BD50	Investigative	[14]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid	DM37C25	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	1.22E-106	5.08	3.56
Chronic obstructive pulmonary disease	CA23	Lung tissue	2.14E-01	0.24	0.22
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	3.35E-06	0.91	1
Renal cancer	2C82	Kidney	2.58E-04	-0.1	-0.27
Coronary artery disease	BA80-BA8Z	Peripheral blood	9.19E-01	-0.03	-0.23
Asthma	CA23	Nasal and bronchial airway	1.31E-06	0.62	0.65

References

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• [2] Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
• [3] Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma. J Microbiol. 2005 Feb;43(1):11-6.
• [4] The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. Int J Oncol. 2002 Feb;20(2):299-303.
• [5] Gelatinase inhibitors: a patent review (2011-2017).Expert Opin Ther Pat. 2018 Jan;28(1):31-46.
• [6] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [7] 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.
• [8] Clinical pipeline report, company report or official report of Vernalis.
• [9] The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3.
• [10] 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.
• [11] Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents. J Med Chem. 2000 Jun 15;43(12):2324-31.
• [12] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [13] 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.
• [14] 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. (Target id: 1636).
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.
• [17] 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.
• [18] Target-Activated Prodrugs (TAPs) for the Autoregulated Inhibition of MMP12. ACS Med Chem Lett. 2012 Jul 14;3(8):653-7.
• [19] 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.