Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTHY57M)

• DTT Name: Matrix metalloproteinase-13 (MMP-13)
• Synonyms: Matrix metalloproteinase 13; Collagenase-3; Collagenase 3
• Gene Name: MMP13
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: MMP13_HUMAN
• TTD ID: T34296
• EC Number: EC 3.4.24.-
• Sequence:
  MHPGVLAAFLFLSWTHCRALPLPSGGDEDDLSEEDLQFAERYLRSYYHPTNLAGILKENA
  ASSMTERLREMQSFFGLEVTGKLDDNTLDVMKKPRCGVPDVGEYNVFPRTLKWSKMNLTY
  RIVNYTPDMTHSEVEKAFKKAFKVWSDVTPLNFTRLHDGIADIMISFGIKEHGDFYPFDG
  PSGLLAHAFPPGPNYGGDAHFDDDETWTSSSKGYNLFLVAAHEFGHSLGLDHSKDPGALM
  FPIYTYTGKSHFMLPDDDVQGIQSLYGPGDEDPNPKHPKTPDKCDPSLSLDAITSLRGET
  MIFKDRFFWRLHPQQVDAELFLTKSFWPELPNRIDAAYEHPSHDLIFIFRGRKFWALNGY
  DILEGYPKKISELGLPKEVKKISAAVHFEDTGKTLLFSGNQVWRYDDTNHIMDKDYPRLI
  EEDFPGIGDKVDAVYEKNGYIYFFNGPIQFEYSIWSNRIVRVMPANSILWC
• Function: Cleaves triple helical collagens, including type I, type II and type III collagen, but has the highest activity with soluble type II collagen. Can also degrade collagen type IV, type XIV and type X. May also function by activating or degrading key regulatory proteins, such as TGFB1 and CTGF. Plays a role in wound healing, tissue remodeling, cartilage degradation, bone development, bone mineralization and ossification. Required for normal embryonic bone development and ossification. Plays a role in the healing of bone fractures via endochondral ossification. Plays a role in wound healing, probably by a mechanism that involves proteolytic activation of TGFB1 and degradation of CTGF. Plays a role in keratinocyte migration during wound healing. May play a role in cell migration and in tumor cell invasion. Plays a role in the degradation of extracellular matrix proteins including fibrillar collagen, fibronectin, TNC and ACAN.
• KEGG Pathway:
  IL-17 signaling pathway (hsa04657)
  Relaxin signaling pathway (hsa04926)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
• 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)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Curcumin	DMQPH29	Solid tumour/cancer	2A00-2F9Z	Phase 3	[1]
Apratastat	DM8W4N9	Rheumatoid arthritis	FA20	Phase 2	[2]
PMID17935984C1	DMO1IHL	Pain	MG30-MG3Z	Clinical trial	[3]

5 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID29130358-Compound-Figure16(9a)	DMKX5R8	N. A.	N. A.	Patented	[4]
PMID29130358-Compound-Figure16(9b)	DMPAQLZ	N. A.	N. A.	Patented	[4]
PMID29130358-Compound-Figure16(9c)	DM0ZRI9	N. A.	N. A.	Patented	[4]
PMID29130358-Compound-Figure18(14)	DM7WXJ9	N. A.	N. A.	Patented	[4]
PMID29130358-Compound-Figure18(14a)	DMHIBTZ	N. A.	N. A.	Patented	[4]

2 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	[5]
RS-130830	DMOTANY	Hepatitis C virus infection	1E51.1	Discontinued in Phase 2	[6]

40 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	[7]
1-(4-Methoxy-benzenesulfonyl)-heptane-3-thiol	DMZWRU7	Discovery agent	N.A.	Investigative	[8]
1-Methyloxy-4-Sulfone-Benzene	DMFR7JW	Discovery agent	N.A.	Investigative	[9]
2-(2-(biphenyl-4-yl)ethylsulfonyl)acetic acid	DM95B4J	Discovery agent	N.A.	Investigative	[7]
2-(4-methoxybenzylthio)-6-methylpyrimidin-4-ol	DMZNPMQ	Discovery agent	N.A.	Investigative	[10]
2-(biphenyl-4-ylsulfonamido)pentanedioic acid	DMH3YBR	Discovery agent	N.A.	Investigative	[10]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide	DMCNV5J	Discovery agent	N.A.	Investigative	[11]
3-(4-Methoxy-benzenesulfonyl)-cyclohexanethiol	DM206M1	Discovery agent	N.A.	Investigative	[12]
3-(4-Methoxy-benzenesulfonyl)-cyclopentanethiol	DMK79U1	Discovery agent	N.A.	Investigative	[12]
3-(4-Methoxy-benzenesulfonyl)-hexane-1-thiol	DMRLAX8	Discovery agent	N.A.	Investigative	[8]
3-(4-Methoxy-benzenesulfonyl)-pentane-1-thiol	DM854IG	Discovery agent	N.A.	Investigative	[8]
3-(4-Methoxy-benzenesulfonyl)-propane-1-thiol	DM7B1VT	Discovery agent	N.A.	Investigative	[8]
3-(4-Phenoxy-benzenesulfonyl)-cyclohexanethiol	DMBKDZ3	Discovery agent	N.A.	Investigative	[12]
3-(4-Phenoxy-benzenesulfonyl)-propane-1-thiol	DM2HBGL	Discovery agent	N.A.	Investigative	[8]
3-Benzenesulfonyl-heptanoic acid hydroxyamide	DM7XDCF	Discovery agent	N.A.	Investigative	[13]
3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide	DMJSOTE	Discovery agent	N.A.	Investigative	[13]
3-Methylpyridine	DMF3JHM	Discovery agent	N.A.	Investigative	[9]
4-(2,2'-bithiophen-5-ylmethyleneamino)phenol	DMRZY0B	Discovery agent	N.A.	Investigative	[1]
4-(4-Methoxy-benzenesulfonyl)-butane-2-thiol	DM5PTB9	Discovery agent	N.A.	Investigative	[8]
4-(methyl(4-phenylthiazol-2-yl)amino)phenol	DMQCMFU	Discovery agent	N.A.	Investigative	[1]
4-amino-3-(4-(hexyloxy)phenyl)-4-oxobutanoic acid	DMGI0YV	Discovery agent	N.A.	Investigative	[10]
5-(4'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid	DMTDNX3	Discovery agent	N.A.	Investigative	[7]
CL82198	DMP3MDS	Discovery agent	N.A.	Investigative	[14]
Ethyl 2-cyano-2-(quinoxalin-2(1H)-ylidene)acetate	DM06AQZ	Discovery agent	N.A.	Investigative	[1]
Hydroxyaminovaline	DMUVCRQ	Discovery agent	N.A.	Investigative	[9]
IK-862	DMJA4UE	Discovery agent	N.A.	Investigative	[15]
MMI270	DM38N2K	Discovery agent	N.A.	Investigative	[16]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide	DM4VADN	Discovery agent	N.A.	Investigative	[11]
N1,N3-bis(3-methoxybenzyl)isophthalamide	DMA5Z7P	Discovery agent	N.A.	Investigative	[17]
N4,N6-dibenzylpyrimidine-4,6-dicarboxamide	DMCR13E	Discovery agent	N.A.	Investigative	[18]
PD-156	DMY5SX9	Inflammation	1A00-CA43.1	Investigative	[19]
PKF-242-484	DMNDLAS	Discovery agent	N.A.	Investigative	[20]
PMID22017539C15	DMWBYNF	Discovery agent	N.A.	Investigative	[21]
Ro-37-9790	DM83QMZ	Discovery agent	N.A.	Investigative	[22]
SL422	DM3I2US	Discovery agent	N.A.	Investigative	[23]
SR-973	DMU48OD	Discovery agent	N.A.	Investigative	[24]
UK-356618	DM02FGH	Discovery agent	N.A.	Investigative	[25]
WAY-151693	DMRWG0C	Discovery agent	N.A.	Investigative	[9]
WAY170523	DMZT8LI	Discovery agent	N.A.	Investigative	[14]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid	DM37C25	Discovery agent	N.A.	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.25E-03	0.76	1.3
Osteoarthritis	FA20	Synovial tissue	7.39E-01	0.13	0.1

References

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• [2] Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1605-9.
• [3] Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13. Bioorg Med Chem Lett. 2007 Dec 1;17(23):6529-34.
• [4] Gelatinase inhibitors: a patent review (2011-2017).Expert Opin Ther Pat. 2018 Jan;28(1):31-46.
• [5] Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia si... J Biol Chem. 2007 Sep 21;282(38):27781-91.
• [6] Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13). Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.
• [7] The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3.
• [8] Discovery of a novel series of selective MMP inhibitors: identification of the gamma-sulfone-thiols. Bioorg Med Chem Lett. 1999 Apr 5;9(7):943-8.
• [9] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [10] 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.
• [11] 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.
• [12] Synthesis and identification of conformationally constrained selective MMP inhibitors. Bioorg Med Chem Lett. 1999 Jul 5;9(13):1757-60.
• [13] Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents. J Med Chem. 2000 Jun 15;43(12):2324-31.
• [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: 1637).
• [15] 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.
• [16] Heterocycle-based MMP inhibitors with P2' substituents. Bioorg Med Chem Lett. 2001 Apr 23;11(8):1009-13.
• [17] Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment ... Bioorg Med Chem Lett. 2010 Jan 15;20(2):576-80.
• [18] Calculation of binding free energies for non-zinc chelating pyrimidine dicarboxamide inhibitors with MMP-13. Bioorg Med Chem Lett. 2009 Jan 1;19(1):47-50.
• [19] 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.
• [20] 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.
• [21] Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13. J Med Chem. 2011 Dec 8;54(23):8174-87.
• [22] 11,21-Bisphenyl-19-norpregnane derivatives are selective antiglucocorticoids, Bioorg. Med. Chem. Lett. 7(17):2299-2302 (1997).
• [23] 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.
• [24] Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63.
• [25] 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.