Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6X50U)

• DTT Name: Matrix metalloproteinase-9 (MMP-9)
• Synonyms: Matrix metalloproteinase 9; GELB; CLG4B; 92 kDa type IV collagenase; 92 kDa gelatinase
• Gene Name: MMP9
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: MMP9_HUMAN
• TTD ID: T54156
• EC Number: EC 3.4.24.35
• Sequence:
  MSLWQPLVLVLLVLGCCFAAPRQRQSTLVLFPGDLRTNLTDRQLAEEYLYRYGYTRVAEM
  RGESKSLGPALLLLQKQLSLPETGELDSATLKAMRTPRCGVPDLGRFQTFEGDLKWHHHN
  ITYWIQNYSEDLPRAVIDDAFARAFALWSAVTPLTFTRVYSRDADIVIQFGVAEHGDGYP
  FDGKDGLLAHAFPPGPGIQGDAHFDDDELWSLGKGVVVPTRFGNADGAACHFPFIFEGRS
  YSACTTDGRSDGLPWCSTTANYDTDDRFGFCPSERLYTQDGNADGKPCQFPFIFQGQSYS
  ACTTDGRSDGYRWCATTANYDRDKLFGFCPTRADSTVMGGNSAGELCVFPFTFLGKEYST
  CTSEGRGDGRLWCATTSNFDSDKKWGFCPDQGYSLFLVAAHEFGHALGLDHSSVPEALMY
  PMYRFTEGPPLHKDDVNGIRHLYGPRPEPEPRPPTTTTPQPTAPPTVCPTGPPTVHPSER
  PTAGPTGPPSAGPTGPPTAGPSTATTVPLSPVDDACNVNIFDAIAEIGNQLYLFKDGKYW
  RFSEGRGSRPQGPFLIADKWPALPRKLDSVFEERLSKKLFFFSGRQVWVYTGASVLGPRR
  LDKLGLGADVAQVTGALRSGRGKMLLFSGRRLWRFDVKAQMVDPRSASEVDRMFPGVPLD
  THDVFQYREKAYFCQDRFYWRVSSRSELNQVDQVGYVTYDILQCPED
• Function: Could play a role in bone osteoclastic resorption. Cleaves KiSS1 at a Gly-|-Leu bond. Cleaves type IV and type V collagen into large C-terminal three quarter fragments and shorter N-terminal one quarter fragments. Degrades fibronectin but not laminin or Pz-peptide. May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration.
• KEGG Pathway:
  TNF signaling pathway (hsa04668)
  Leukocyte transendothelial migration (hsa04670)
  Estrogen signaling pathway (hsa04915)
  Hepatitis B (hsa05161)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Bladder cancer (hsa05219)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DTT

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Andecaliximab	DMLDB1X	Gastric adenocarcinoma	2B72	Phase 3	[2]
Curcumin	DMQPH29	Solid tumour/cancer	2A00-2F9Z	Phase 3	[1]
DP-b99	DM97S10	Stroke	8B20	Phase 3	[3]
GS-5745	DMP8MDW	Gastric adenocarcinoma	2B72	Phase 3	[4]
BLZ-100	DMFKA4G	Glioma	2A00.0	Phase 1/2	[5]
Neovastat	DMXTYWJ	Non-small-cell lung cancer	2C25.Y	Phase 1	[6]

8 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID29130358-Compound-Figure13(4)	DMDFPIO	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-Figure17(10)	DMVA15O	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-Figure17(11)	DMSZA9L	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-Figure17(12)	DMML4PA	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-Figure17(13)	DM2QRIW	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-Figure18(14a)	DMHIBTZ	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-LonimacranthoideVII	DMOGIAU	N. A.	N. A.	Patented	[7]
PMID29130358-Compound-SB-3CT	DMC64XQ	N. A.	N. A.	Patented	[7]

7 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Galarubicin	DMTNYSF	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[8]
GM6001	DM7V9CT	Corneal ulcer	9A76	Discontinued in Phase 2	[9]
RS-130830	DMOTANY	Hepatitis C virus infection	1E51.1	Discontinued in Phase 2	[10]
CDP-845	DMGMS2D	Solid tumour/cancer	2A00-2F9Z	Terminated	[12]
CT-1746	DM84KOY	Colorectal cancer	2B91.Z	Terminated	[13]
RO-319790	DML3NEU	Rheumatoid arthritis	FA20	Terminated	[14]
SC-44463	DMBPNKT	N. A.	N. A.	Terminated	[15]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DX-2802	DM8YSW7	Solid tumour/cancer	2A00-2F9Z	Preclinical	[11]

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	[16]
2-(4'-chloro-biphenyl-4-sulfonyl)-pentanoic acid	DMQAVM4	Discovery agent	N.A.	Investigative	[17]
2-(biphenyl-4-ylsulfonamido)pentanedioic acid	DMH3YBR	Discovery agent	N.A.	Investigative	[18]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide	DMCNV5J	Discovery agent	N.A.	Investigative	[19]
2-Amino-N,3,3-Trimethylbutanamide	DM3YI9P	Discovery agent	N.A.	Investigative	[20]
3-(4-(2-phenylethynyl)benzoyl)pentanoic acid	DMQDPHT	Discovery agent	N.A.	Investigative	[21]
3-(4-Phenylethynylbenzoyl)nonanoic acid	DMXL0J5	Discovery agent	N.A.	Investigative	[21]
4-amino-3-(4-(hexyloxy)phenyl)-4-oxobutanoic acid	DMGI0YV	Discovery agent	N.A.	Investigative	[18]
5-(4-Phenoxy-phenyl)-pyrimidine-2,4,6-trione	DM05OMF	Discovery agent	N.A.	Investigative	[22]
5-Biphenyl-4-yl-5-ethyl-pyrimidine-2,4,6-trione	DMFAITE	Discovery agent	N.A.	Investigative	[22]
5-Biphenyl-4-yl-5-hexyl-pyrimidine-2,4,6-trione	DMI2PXO	Discovery agent	N.A.	Investigative	[22]
5-Hexyl-5-phenyl-pyrimidine-2,4,6-trione	DM4S86L	Discovery agent	N.A.	Investigative	[22]
5-Methyl-5-phenyl-pyrimidine-2,4,6-trione	DMRMKXD	Discovery agent	N.A.	Investigative	[22]
ARP100	DM6KQXF	Discovery agent	N.A.	Investigative	[23]
Carboxylated glucosamine	DM105YR	Discovery agent	N.A.	Investigative	[24]
Folate gamma-hydroxamic acid	DMJ4F3Q	Discovery agent	N.A.	Investigative	[25]
IK-862	DMJA4UE	Discovery agent	N.A.	Investigative	[26]
Methotrexate gamma-hydroxamic acid	DM8P526	Discovery agent	N.A.	Investigative	[25]
Methotrexate gamma-L-phenylalaninehydroxamic acid	DMELK2A	Discovery agent	N.A.	Investigative	[25]
Methotrexate gamma-L-proline-hydroxamic acid	DMPYJLA	Discovery agent	N.A.	Investigative	[25]
MMI270	DM38N2K	Discovery agent	N.A.	Investigative	[27]
N-hydroxy-2,3-bis(phenylsulfonamido)propanamide	DMZWIVJ	Discovery agent	N.A.	Investigative	[28]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide	DM4VADN	Discovery agent	N.A.	Investigative	[19]
N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide	DMWXUCT	Discovery agent	N.A.	Investigative	[29]
N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl)	DMA6EPH	Discovery agent	N.A.	Investigative	[29]
PMID15055993C1a	DM9V6YK	Discovery agent	N.A.	Investigative	[30]
PMID23631440C29e	DMM92IB	Discovery agent	N.A.	Investigative	[31]
Ro 28-2653	DMDC4HY	Discovery agent	N.A.	Investigative	[32]
Ro-37-9790	DM83QMZ	Discovery agent	N.A.	Investigative	[33]
Roche 28-2653	DMD4JHK	Discovery agent	N.A.	Investigative	[32]
SL422	DM3I2US	Discovery agent	N.A.	Investigative	[34]
SR-973	DMU48OD	Discovery agent	N.A.	Investigative	[35]
UK-356618	DM02FGH	Discovery agent	N.A.	Investigative	[36]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid	DM37C25	Discovery agent	N.A.	Investigative	[19]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Renal cancer	2C82	Kidney	1.12E-10	1.15	3.45
Lung cancer	2C82	Lung tissue	3.53E-54	2.03	1.94
Rheumatoid arthritis	FA20	Synovial tissue	7.66E-05	0.81	1.83
Ovarian cancer	2C82	Ovarian tissue	1.15E-07	1.57	3.98
Osteoarthritis	FA20	Synovial tissue	2.59E-01	0.11	0.25

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Matrix metalloproteinase-9 (MMP-9) DME Info
• Gene Name: MMP9

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amylin	DMWDEN0	N. A.	N. A.	Phase 4	[37]

References

• [1] Synthesis and biological evaluation of curcuminoid pyrazoles as new therapeutic agents in inflammatory bowel disease: effect on matrix metalloprote... Bioorg Med Chem. 2009 Feb 1;17(3):1290-6.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] DP-b99 modulates matrix metalloproteinase activity and neuronal plasticity. PLoS One. 2014 Jun 11;9(6):e99789.
• [4] National Cancer Institute Drug Dictionary (drug id 747683).
• [5] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [6] Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
• [7] Gelatinase inhibitors: a patent review (2011-2017).Expert Opin Ther Pat. 2018 Jan;28(1):31-46.
• [8] Inhibitory effect of DA-125, a new anthracyclin analog antitumor agent, on the invasion of human fibrosarcoma cells by down-regulating the matrix m... Biochem Pharmacol. 2005 Dec 19;71(1-2):21-31.
• [9] Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with i... Bioorg Med Chem. 2008 Sep 15;16(18):8745-59.
• [10] Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13). Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.
• [11] Clinical pipeline report, company report or official report of DeepDyve.
• [12] Clinical potential of matrix metalloprotease inhibitors. Drugs R D. 1999 Feb;1(2):117-29.
• [13] Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor. Clin Exp Metastasis. 1997 Mar;15(2):184-95.
• [14] The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett. 1998 May 19;8(10):1163-8.
• [15] Design and synthesis of a series of (2R)-N(4)-hydroxy-2-(3-hydroxybenzyl)-N(1)- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivati... J Med Chem. 2001 Oct 11;44(21):3347-50.
• [16] The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3.
• [17] Synthesis and SAR of alpha-sulfonylcarboxylic acids as potent matrix metalloproteinase inhibitors. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3096-100.
• [18] Ranking the selectivity of PubChem screening hits by activity-based protein profiling: MMP13 as a case study. Bioorg Med Chem. 2009 Feb 1;17(3):1101-8.
• [19] 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.
• [20] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [21] 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.
• [22] Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors. Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.
• [23] Amber force field implementation, molecular modelling study, synthesis and MMP-1/MMP-2 inhibition profile of (R)- and (S)-N-hydroxy-2-(N-isopropoxy... Bioorg Med Chem. 2006 Jun 15;14(12):4260-76.
• [24] Carboxy derivatized glucosamine is a potent inhibitor of matrix metalloproteinase-9 in HT1080 cells. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3105-10.
• [25] Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs. Bioorg Med Chem. 2007 Feb 1;15(3):1266-74.
• [26] Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structu... J Med Chem. 2002 Nov 7;45(23):4954-7.
• [27] Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors. Bioorg Med Chem Lett. 1999 Jun 21;9(12):1691-6.
• [28] Novel bis-(arylsulfonamide) hydroxamate-based selective MMP inhibitors. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3333-7.
• [29] Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation. Bioorg Med Chem. 2008 Jan 1;16(1):530-5.
• [30] Azasugar-based MMP/ADAM inhibitors as antipsoriatic agents. J Med Chem. 2004 Apr 8;47(8):1930-8.
• [31] Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core. J Med Chem. 2013 Jun 13;56(11):4357-73.
• [32] The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model. Oncogene. 2002 Mar 27;21(13):2089-96.
• [33] 11,21-Bisphenyl-19-norpregnane derivatives are selective antiglucocorticoids, Bioorg. Med. Chem. Lett. 7(17):2299-2302 (1997).
• [34] Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J Med Chem. 2001 Aug 2;44(16):2636-60.
• [35] Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63.
• [36] A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers. J Med Chem. 2003 Jul 31;46(16):3514-25.
• [37] Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide. J Biol Chem. 2013 Feb 1;288(5):3553-9.