Target Information

Target General Infomation
Target ID
T17758
Former ID
TTDC00312
Target Name
Urokinase-type plasminogen activator
Gene Name
PLAU
Synonyms
U-plasminogen activator; UPA; PLAU
Target Type
Successful
Disease Breast cancer [ICD9: 174, 175; ICD10: C50]
Cerebrovascular ischaemia [ICD9: 434.91; ICD10: I61-I63]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Deep venous thrombosis; Pulmonary embolism; Myocardial infarction [ICD9: 410, 415.1, 437.6, 444.9, 453, 453.40, 671.5, 671.9; ICD10: I21, I22, I26, I74, I80-I82, I80.2, I82, O88, T79.0-T79.1]
Myocardial infarction; Thrombolysis [ICD9:410, 415.1, 434.91, 459.9; ICD10: I21, I22, I21-I22, I26, I61-I63, I99.9]
Myocardial infarction [ICD9: 410; ICD10: I21, I22]
Myocardial ischemia; Reperfusion injury [ICD9: 459.89; ICD10: I99.8]
Myocardial hypertrophy [ICD10: I51.7]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Thromboembolism [ICD9: 437.6, 453, 671.5, 671.9; ICD10: I80-I82]
Thrombin deficiency [ICD9: 437.6, 444.9, 453, 671.5, 671.9; ICD10: I74, I80-I82, I82, O88, T79.0-T79.1]
Unspecified [ICD code not available]
Function
Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
BioChemical Class
Peptidase
Target Validation
T17758
UniProt ID
P00749
EC Number
EC 3.4.21.73
Sequence
MRALLARLLLCVLVVSDSKGSNELHQVPSNCDCLNGGTCVSNKYFSNIHWCNCPKKFGGQ
HCEIDKSKTCYEGNGHFYRGKASTDTMGRPCLPWNSATVLQQTYHAHRSDALQLGLGKHN
YCRNPDNRRRPWCYVQVGLKPLVQECMVHDCADGKKPSSPPEELKFQCGQKTLRPRFKII
GGEFTTIENQPWFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLG
RSRLNSNTQGEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICL
PSMYNDPQFGTSCEITGFGKENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKML
CAADPQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR
SHTKEENGLAL
Drugs and Mode of Action
Drug(s) Pro-urokinase Drug Info Approved Thrombin deficiency [1]
Urokinase Drug Info Approved Deep venous thrombosis; Pulmonary embolism; Myocardial infarction [2]
PAI-1 Drug Info Phase 4 Discovery agent [3]
Amediplase Drug Info Phase 3 Myocardial infarction; Thrombolysis [4], [2]
Saruplase Drug Info Phase 2 Thromboembolism [5]
Upamostat Drug Info Phase 2 Breast cancer [6], [7]
HTU-PA Drug Info Phase 1/2 Cerebrovascular ischaemia [8]
compound 4 Drug Info Clinical trial Myocardial ischemia; Reperfusion injury [9], [10]
UK-356202 Drug Info Clinical trial Myocardial hypertrophy [11]
PAI-2 Drug Info Discontinued in Phase 2 Discovery agent [12]
WX-UK1 Drug Info Discontinued in Phase 1/2 Solid tumours [13], [14]
B-428 Drug Info Terminated Cancer [15]
Inhibitor (2R)-1-(2,6-dimethylphenoxy)propan-2-amine Drug Info [16]
(3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone Drug Info [17]
(3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info [17]
(4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone Drug Info [17]
(4-guanidino-benzyl)-carbamic acid benzyl ester Drug Info [18]
(4-nitro-1H-pyrazol-1-yl)(o-tolyl)methanone Drug Info [17]
(4-nitro-1H-pyrazol-1-yl)(phenyl)methanone Drug Info [17]
1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide Drug Info [17]
1-guanidino-7-isoquinolinesulphonamide Drug Info [19]
1-guanidino-N-phenyl-7-isoquinolinesulphonamide Drug Info [19]
1-[4-(2-oxo-2-phenylethyl)phenyl]guanidine Drug Info [16]
2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine Drug Info [20]
2-amidino-4-iodobenzothiophene Drug Info [21]
2-Amino-5-Hydroxy-Benzimidazole Drug Info [22]
2-nas-phe(3-am)-4-(2-guanidinoethyl)piperidine Drug Info [23]
4-chloro-1-guanidino-7-isoquinolinesulphonamide Drug Info [19]
4-iodobenzo[b]thiophene 2-carboxamidine Drug Info [24]
4-Iodobenzo[B]Thiophene-2-Carboxamidine Drug Info [16]
4-methoxy-N'-(2-phenylacetyl)benzohydrazide Drug Info [17]
5-Methylsulfanyl-thiophene-2-carboxamidine Drug Info [21]
6-(N-Phenylcarbamyl)-2-Naphthalenecarboxamidine Drug Info [22]
B-428 Drug Info [25]
Benzamidine Drug Info [22]
compound 4 Drug Info [9]
CRA_10655 Drug Info [16]
CRA_8696 Drug Info [16]
Fucose Drug Info [22]
N-(1-Adamantyl)-N'-(4-Guanidinobenzyl)Urea Drug Info [22]
PAI-1 Drug Info [26]
PAI-2 Drug Info [27]
Recombinant human pro-urokinase Drug Info [28]
Thieno[2,3-B]Pyridine-2-Carboxamidine Drug Info [16]
UK-356202 Drug Info [11]
UPA-targeted oncolytic Sendai virus Drug Info [28]
Upamostat Drug Info [6]
WX-UK1 Drug Info [29]
Activator Amediplase Drug Info [2]
ATN-658 Drug Info [28]
HTU-PA Drug Info [30]
Saruplase Drug Info [5]
Modulator ATF-HI-8 Drug Info
B-623 Drug Info
Pro-urokinase Drug Info [28]
Urokinase Drug Info [31]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway NF-kappa B signaling pathway
Complement and coagulation cascades
Transcriptional misregulation in cancer
Proteoglycans in cancer
MicroRNAs in cancer
NetPath Pathway IL2 Signaling Pathway
EGFR1 Signaling Pathway
PANTHER Pathway Blood coagulation
Plasminogen activating cascade
CCKR signaling map ST
Pathway Interaction Database Beta1 integrin cell surface interactions
E2F transcription factor network
Beta3 integrin cell surface interactions
Osteopontin-mediated events
Validated transcriptional targets of AP1 family members Fra1 and Fra2
amb2 Integrin signaling
ATF-2 transcription factor network
AP-1 transcription factor network
Beta2 integrin cell surface interactions
Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling
Beta5 beta6 beta7 and beta8 integrin cell surface interactions
FGF signaling pathway
Reactome Dissolution of Fibrin Clot
WikiPathways DNA Damage Response (only ATM dependent)
Senescence and Autophagy in Cancer
Complement and Coagulation Cascades
Endochondral Ossification
Wnt Signaling Pathway
Wnt Signaling Pathway and Pluripotency
Blood Clotting Cascade
Dissolution of Fibrin Clot
Osteopontin Signaling
References
REF 1Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 2Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90.
REF 3ClinicalTrials.gov (NCT00770328) The Effects of Pentoxifylline on PAI-1 in an Obese Population. U.S. National Institutes of Health.
REF 4Amediplase: CGP 42935, K2tu-PA, MEN 9036. BioDrugs. 2002;16(5):378-9.
REF 5Pharmacokinetics 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.
REF 6Phase 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.
REF 7(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. (Ligand id: 6497).
REF 8ClinicalTrials.gov (NCT00418275) Safety Study of a Recombinant Human Plasminogen Activator to Treat Acute Ischemic Stroke.. U.S. National Institutes of Health.
REF 9Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator. J Med Chem. 2008 Jan 24;51(2):183-6.
REF 10(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. (Ligand id: 6545).
REF 11Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30.Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines.
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004611)
REF 13(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. (Ligand id: 6498).
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012176)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009078)
REF 16The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 17J Med Chem. 2007 Oct 4;50(20):4928-38. Epub 2007 Sep 12.N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase.
REF 18J Med Chem. 2007 Dec 27;50(26):6638-46. Epub 2007 Dec 1.Small, potent, and selective diaryl phosphonate inhibitors for urokinase-type plasminogen activator with in vivo antimetastatic properties.
REF 19J Med Chem. 2007 May 17;50(10):2341-51. Epub 2007 Apr 21.Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines.
REF 20J Med Chem. 2001 Aug 16;44(17):2753-71.Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasminogen activator and factor Xa.
REF 21Bioorg Med Chem Lett. 2002 Feb 11;12(3):491-5.Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.
REF 22How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 23J Med Chem. 2006 Jul 13;49(14):4116-26.Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase.
REF 24Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator. Chem Biol. 2000 Apr;7(4):299-312.
REF 25Natural and synthetic inhibitors of the tumor-associated serine protease urokinase-type plasminogen activator. Adv Exp Med Biol. 2000;477:331-41.
REF 26Urokinase-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.
REF 27Topological localization of plasminogen activator inhibitor type 2. Cytometry. 2000 May 1;40(1):32-41.
REF 28(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).
REF 29Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system. Int J Cancer. 2004 Jul 20;110(6):815-24.
REF 30Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells. J Biol Chem. 1986 Mar 25;261(9):4352-7.
REF 31Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

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