Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGY7WI)

• DTT Name: Urokinase-type plasminogen activator (PLAU)
• Synonyms: UPA; U-plasminogen activator
• Gene Name: PLAU
• DTT Type: Successful target; [1]
• BioChemical Class: Peptidase
• UniProt ID: UROK_HUMAN
• TTD ID: T17758
• EC Number: EC 3.4.21.73
• Sequence:
  MRALLARLLLCVLVVSDSKGSNELHQVPSNCDCLNGGTCVSNKYFSNIHWCNCPKKFGGQ
  HCEIDKSKTCYEGNGHFYRGKASTDTMGRPCLPWNSATVLQQTYHAHRSDALQLGLGKHN
  YCRNPDNRRRPWCYVQVGLKPLVQECMVHDCADGKKPSSPPEELKFQCGQKTLRPRFKII
  GGEFTTIENQPWFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLG
  RSRLNSNTQGEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICL
  PSMYNDPQFGTSCEITGFGKENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKML
  CAADPQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR
  SHTKEENGLAL
• Function: Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Complement and coagulation cascades (hsa04610)
  Transcriptional misregulation in cancer (hsa05202)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway: Dissolution of Fibrin Clot (R-HSA-75205)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pro-urokinase	DMGKT2L	Thrombin deficiency	3B14.Z	Approved	[1]
Urokinase	DM0GOUD	Myocardial infarction	BA41-BA43	Approved	[2]
PAI-1	DMY2AEF	N. A.	N. A.	Phase 4	[3]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amediplase	DM4FPM3	Myocardial infarction	BA41-BA43	Phase 3	[4]
Saruplase	DM1M0PR	Thrombosis	DB61-GB90	Phase 2	[5]
Upamostat	DMFZULI	Breast cancer	2C60-2C65	Phase 2	[6]
HTU-PA	DMNHE43	Cerebrovascular ischaemia	8B1Z	Phase 1/2	[7]
PMID18163548C4	DMHPME3	Myocardial ischemia	BA6Z	Clinical trial	[8]
UK-356202	DMSRK2A	Myocardial hypertrophy	BC45	Clinical trial	[9]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PAI-2	DMRSMW8	N. A.	N. A.	Discontinued in Phase 2	[10]
WX-UK1	DM8Q2ZR	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1/2	[11]
B-428	DME6OFU	Solid tumour/cancer	2A00-2F9Z	Terminated	[12]

30 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2R)-1-(2,6-dimethylphenoxy)propan-2-amine	DMQ2XUE	Discovery agent	N.A.	Investigative	[13]
(3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone	DMNVDLI	Discovery agent	N.A.	Investigative	[14]
(3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone	DMT9FZD	Discovery agent	N.A.	Investigative	[14]
(4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone	DM31OSD	Discovery agent	N.A.	Investigative	[14]
(4-guanidino-benzyl)-carbamic acid benzyl ester	DM0KXP1	Discovery agent	N.A.	Investigative	[15]
(4-nitro-1H-pyrazol-1-yl)(o-tolyl)methanone	DMBPL3J	Discovery agent	N.A.	Investigative	[14]
(4-nitro-1H-pyrazol-1-yl)(phenyl)methanone	DMIDUO9	Discovery agent	N.A.	Investigative	[14]
1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide	DMG5MNZ	Discovery agent	N.A.	Investigative	[14]
1-guanidino-7-isoquinolinesulphonamide	DM48TIN	Discovery agent	N.A.	Investigative	[16]
1-guanidino-N-phenyl-7-isoquinolinesulphonamide	DMTF1HL	Discovery agent	N.A.	Investigative	[16]
1-[4-(2-oxo-2-phenylethyl)phenyl]guanidine	DME1R96	Discovery agent	N.A.	Investigative	[13]
2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine	DM3UMYD	Discovery agent	N.A.	Investigative	[17]
2-Amino-5-Hydroxy-Benzimidazole	DMA7ZOW	Discovery agent	N.A.	Investigative	[18]
2-nas-phe(3-am)-4-(2-guanidinoethyl)piperidine	DMFXKN1	Discovery agent	N.A.	Investigative	[19]
4-chloro-1-guanidino-7-isoquinolinesulphonamide	DMMIA36	Discovery agent	N.A.	Investigative	[16]
4-iodobenzo[b]thiophene 2-carboxamidine	DMXAEGF	N. A.	N. A.	Investigative	[20]
4-methoxy-N'-(2-phenylacetyl)benzohydrazide	DMF079L	Discovery agent	N.A.	Investigative	[14]
5-Methylsulfanyl-thiophene-2-carboxamidine	DM3MVSD	Discovery agent	N.A.	Investigative	[21]
6-(N-Phenylcarbamyl)-2-Naphthalenecarboxamidine	DMHM0RW	Discovery agent	N.A.	Investigative	[18]
ATF-HI-8	DMPJRHX	Discovery agent	N.A.	Investigative	[22]
ATN-658	DMR2M7L	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]
B-623	DMIUD0L	Discovery agent	N.A.	Investigative	[23]
Benzamidine	DM37GWL	Discovery agent	N.A.	Investigative	[18]
CRA_10655	DM70YRT	Discovery agent	N.A.	Investigative	[13]
CRA_8696	DM3IZOP	Discovery agent	N.A.	Investigative	[13]
Fucose	DMAHMSV	N. A.	N. A.	Investigative	[18]
N-(1-Adamantyl)-N'-(4-Guanidinobenzyl)Urea	DMD6N8V	Discovery agent	N.A.	Investigative	[18]
Recombinant human pro-urokinase	DMVJLR3	Myocardial infarction	BA41-BA43	Investigative	[1]
Thieno[2,3-B]Pyridine-2-Carboxamidine	DMUL2FW	Discovery agent	N.A.	Investigative	[13]
UPA-targeted oncolytic Sendai virus	DMR46C8	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	5.32E-70	1.07	1.82

References

• [1] 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: 2393).
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer. J Natl Cancer Inst. 1995 May 17;87(10):751-6.
• [4] Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90.
• [5] Pharmacokinetics and pharmacodynamics of saruplase, an unglycosylated single-chain urokinase-type plasminogen activator, in patients with acute myocardial infarction. Thromb Haemost. 1994 Nov;72(5):740-4.
• [6] Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer. Br J Cancer. 2013 Mar 5;108(4):766-70.
• [7] Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells. J Biol Chem. 1986 Mar 25;261(9):4352-7.
• [8] Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator. J Med Chem. 2008 Jan 24;51(2):183-6.
• [9] Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30.
• [10] Topological localization of plasminogen activator inhibitor type 2. Cytometry. 2000 May 1;40(1):32-41.
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• [13] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [14] N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. J Med Chem. 2007 Oct 4;50(20):4928-38.
• [15] Small, potent, and selective diaryl phosphonate inhibitors for urokinase-type plasminogen activator with in vivo antimetastatic properties. J Med Chem. 2007 Dec 27;50(26):6638-46.
• [16] Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. J Med Chem. 2007 May 17;50(10):2341-51.
• [17] Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasmi... J Med Chem. 2001 Aug 16;44(17):2753-71.
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• [19] Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. J Med Chem. 2006 Jul 13;49(14):4116-26.
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• [21] Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors. Bioorg Med Chem Lett. 2002 Feb 11;12(3):491-5.
• [22] Inhibitory effect of a conjugate between human urokinase and urinary trypsin inhibitor on tumor cell invasion in vitro. J Biol Chem. 1995 Apr 7;270(14):8361-6.
• [23] Angiostatic activity of synthetic inhibitors of urokinase type plasminogen activator. Oncol Rep. 1999 May-Jun;6(3):523-6.