Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUZ2L5)

• DTT Name: Matrix metalloproteinase-3 (MMP-3)
• Synonyms: Transin-1; Stromelysin-1; STMY1; SL-1; MMP-3
• Gene Name: MMP3
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Peptidase
• UniProt ID: MMP3_HUMAN
• TTD ID: T86702
• EC Number: EC 3.4.24.17
• Sequence:
  MKSLPILLLLCVAVCSAYPLDGAARGEDTSMNLVQKYLENYYDLKKDVKQFVRRKDSGPV
  VKKIREMQKFLGLEVTGKLDSDTLEVMRKPRCGVPDVGHFRTFPGIPKWRKTHLTYRIVN
  YTPDLPKDAVDSAVEKALKVWEEVTPLTFSRLYEGEADIMISFAVREHGDFYPFDGPGNV
  LAHAYAPGPGINGDAHFDDDEQWTKDTTGTNLFLVAAHEIGHSLGLFHSANTEALMYPLY
  HSLTDLTRFRLSQDDINGIQSLYGPPPDSPETPLVPTEPVPPEPGTPANCDPALSFDAVS
  TLRGEILIFKDRHFWRKSLRKLEPELHLISSFWPSLPSGVDAAYEVTSKDLVFIFKGNQF
  WAIRGNEVRAGYPRGIHTLGFPPTVRKIDAAISDKEKNKTYFFVEDKYWRFDEKRNSMEP
  GFPKQIAEDFPGIDSKIDAVFEEFGFFYFFTGSSQLEFDPNAKKVTHTLKSNSWLNC
• Function: Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.
• KEGG Pathway:
  TNF signaling pathway (hsa04668)
  Transcriptional misregulation in cancer (hsa05202)
  Rheumatoid arthritis (hsa05323)
• 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)
  EGFR Transactivation by Gastrin (R-HSA-2179392)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DTT

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID29130358-Compound-Figure10(2a)	DMFWXPS	N. A.	N. A.	Patented	[1]

7 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GM6001	DM7V9CT	Corneal ulcer	9A76	Discontinued in Phase 2	[2]
PG-530742	DMELXBQ	Myocardial infarction	BA41-BA43	Discontinued in Phase 2	[3]
RS-130830	DMOTANY	Hepatitis C virus infection	1E51.1	Discontinued in Phase 2	[4]
BB-1101	DM7GH5Z	Multiple sclerosis	8A40	Terminated	[6]
L-696418	DMV785R	N. A.	N. A.	Terminated	[7]
RO-319790	DML3NEU	Rheumatoid arthritis	FA20	Terminated	[8]
SC-44463	DMBPNKT	N. A.	N. A.	Terminated	[9]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Batimastat	DM92VRP	Idiopathic pulmonary fibrosis	CB03.4	Preclinical	[5]

17 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-Methyloxy-4-Sulfone-Benzene	DMFR7JW	Discovery agent	N.A.	Investigative	[10]
3-Methylpyridine	DMF3JHM	Discovery agent	N.A.	Investigative	[10]
5-Biphenyl-4-yl-5-ethyl-pyrimidine-2,4,6-trione	DMFAITE	Discovery agent	N.A.	Investigative	[11]
8-chloro-quinoline-3-carbonitrile	DMFNUHQ	Discovery agent	N.A.	Investigative	[12]
AM-2S	DMZ46GI	Discovery agent	N.A.	Investigative	[13]
CM-352	DMXA8K1	Discovery agent	N.A.	Investigative	[14]
FUTOENONE	DMFBP7C	Discovery agent	N.A.	Investigative	[15]
Hydroxyaminovaline	DMUVCRQ	Discovery agent	N.A.	Investigative	[10]
IK-862	DMJA4UE	Discovery agent	N.A.	Investigative	[16]
MMI270	DM38N2K	Discovery agent	N.A.	Investigative	[17]
PD-169469	DMU3OR1	Discovery agent	N.A.	Investigative	[18]
PKF-242-484	DMNDLAS	Discovery agent	N.A.	Investigative	[19]
PNU-107859	DMS5XRY	Discovery agent	N.A.	Investigative	[20]
PNU-142372	DMEI0S7	Discovery agent	N.A.	Investigative	[21]
Ro-37-9790	DM83QMZ	Discovery agent	N.A.	Investigative	[22]
RS-39066	DM2SCM7	Discovery agent	N.A.	Investigative	[23]
UK-356618	DM02FGH	Discovery agent	N.A.	Investigative	[24]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	3.83E-01	1.44	0.67
Osteoarthritis	FA20	Synovial tissue	9.81E-01	0.17	0.06
Ovarian cancer	2C82	Ovarian tissue	2.22E-02	0.1	0.53
Lung cancer	2C82	Lung tissue	4.17E-112	0.66	2.63

References

• [1] Gelatinase inhibitors: a patent review (2011-2017).Expert Opin Ther Pat. 2018 Jan;28(1):31-46.
• [2] 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.
• [3] Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart fail... Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2522-7.
• [4] Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13). Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.
• [5] Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. Cancer Res. 1994 Sep 1;54(17):4726-8.
• [6] Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution. Bioorg Med Chem Lett. 1998 Jun 16;8(12):1443-8.
• [7] Inhibition of matrix metalloproteinases by N-carboxyalkyl peptides containing extended alkyl residues At P1', Bioorg. Med. Chem. Lett. 5(6):539-542 (1995).
• [8] 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.
• [9] Amide surrogates of matrix metalloproteinase inhibitors: Urea and sulfonamide mimics, Bioorg. Med. Chem. Lett. 7(18):2331-2336 (1997).
• [10] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [11] Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors. Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.
• [12] Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. J Biol Chem. 2007 Nov 16;282(46):33295-304.
• [13] Synthesis of hydroxypyrone- and hydroxythiopyrone-based matrix metalloproteinase inhibitors: developing a structure-activity relationship. Bioorg Med Chem Lett. 2009 Apr 1;19(7):1970-6.
• [14] Discovery and safety profiling of a potent preclinical candidate, (4-[4-[[(3R)-3-(hydroxycarbamoyl)-8-azaspiro[4.5]decan-3-yl]sulfonyl]phenoxy]-N-methylbenzamide) (CM-352), for the prevention and treatment of hemorrhage. J Med Chem. 2015 Apr 9;58(7):2941-57.
• [15] Inhibition of metalloproteinase by futoenone derivatives, Bioorg. Med. Chem. Lett. 5(15):1637-1642 (1995).
• [16] 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.
• [17] Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer. 2002 Sep;2(9):657-72.
• [18] Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates. J Med Chem. 2006 Feb 9;49(3):923-31.
• [19] A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors. Bioorg Med Chem Lett. 2006 May 15;16(10):2632-6.
• [20] A molecular basis for the selectivity of thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A from generalized born molecular dynamics s... J Med Chem. 2004 Jun 3;47(12):3065-74.
• [21] Protease inhibitors: synthesis of matrix metalloproteinase and bacterial collagenase inhibitors incorporating 5-amino-2-mercapto-1,3,4-thiadiazole ... Bioorg Med Chem Lett. 2002 Oct 7;12(19):2667-72.
• [22] 11,21-Bisphenyl-19-norpregnane derivatives are selective antiglucocorticoids, Bioorg. Med. Chem. Lett. 7(17):2299-2302 (1997).
• [23] Design, synthesis, activity, and structure of a novel class of matrix metalloproteinase inhibitors containing a heterocyclic P2 P3 Bioorg. Med. Chem. Lett. 6(13):1541-1542 (1996).
• [24] 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.