Target Information
| Target General Information | Top | |||||
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| Target ID |
T17758
(Former ID: TTDC00312)
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| Target Name |
Urokinase-type plasminogen activator (PLAU)
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| Synonyms |
UPA; U-plasminogen activator
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| Gene Name |
PLAU
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Inherited coagulation factor deficiency [ICD-11: 3B14] | |||||
| 2 | Myocardial infarction [ICD-11: BA41-BA43] | |||||
| Function |
Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.21.73
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| Sequence |
MRALLARLLLCVLVVSDSKGSNELHQVPSNCDCLNGGTCVSNKYFSNIHWCNCPKKFGGQ
HCEIDKSKTCYEGNGHFYRGKASTDTMGRPCLPWNSATVLQQTYHAHRSDALQLGLGKHN YCRNPDNRRRPWCYVQVGLKPLVQECMVHDCADGKKPSSPPEELKFQCGQKTLRPRFKII GGEFTTIENQPWFAAIYRRHRGGSVTYVCGGSLISPCWVISATHCFIDYPKKEDYIVYLG RSRLNSNTQGEMKFEVENLILHKDYSADTLAHHNDIALLKIRSKEGRCAQPSRTIQTICL PSMYNDPQFGTSCEITGFGKENSTDYLYPEQLKMTVVKLISHRECQQPHYYGSEVTTKML CAADPQWKTDSCQGDSGGPLVCSLQGRMTLTGIVSWGRGCALKDKPGVYTRVSHFLPWIR SHTKEENGLAL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| ADReCS ID | BADD_A01328 | |||||
| HIT2.0 ID | T84P70 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Pro-urokinase | Drug Info | Approved | Thrombin deficiency | [2] | |
| 2 | Urokinase | Drug Info | Approved | Myocardial infarction | [3] | |
| Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | Amediplase | Drug Info | Phase 3 | Thrombosis | [3], [4] | |
| 2 | Saruplase | Drug Info | Phase 2 | Thrombosis | [5] | |
| 3 | Upamostat | Drug Info | Phase 2 | Breast cancer | [6], [7] | |
| 4 | HTU-PA | Drug Info | Phase 1/2 | Cerebrovascular ischaemia | [8] | |
| 5 | PMID18163548C4 | Drug Info | Clinical trial | Reperfusion injury | [9], [10] | |
| 6 | UK-356202 | Drug Info | Clinical trial | Myocardial hypertrophy | [11] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | WX-UK1 | Drug Info | Discontinued in Phase 1/2 | Solid tumour/cancer | [12], [13] | |
| 2 | B-428 | Drug Info | Terminated | Solid tumour/cancer | [14] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Pro-urokinase | Drug Info | [1] | |||
| 2 | Urokinase | Drug Info | [15] | |||
| 3 | ATF-HI-8 | Drug Info | [30] | |||
| 4 | B-623 | Drug Info | [31] | |||
| Inhibitor | [+] 34 Inhibitor drugs | + | ||||
| 1 | PAI-1 | Drug Info | [16] | |||
| 2 | Upamostat | Drug Info | [7] | |||
| 3 | PMID18163548C4 | Drug Info | [9] | |||
| 4 | UK-356202 | Drug Info | [11] | |||
| 5 | PAI-2 | Drug Info | [18] | |||
| 6 | WX-UK1 | Drug Info | [19] | |||
| 7 | B-428 | Drug Info | [20] | |||
| 8 | (2R)-1-(2,6-dimethylphenoxy)propan-2-amine | Drug Info | [21] | |||
| 9 | (3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone | Drug Info | [22] | |||
| 10 | (3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone | Drug Info | [22] | |||
| 11 | (4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone | Drug Info | [22] | |||
| 12 | (4-guanidino-benzyl)-carbamic acid benzyl ester | Drug Info | [23] | |||
| 13 | (4-nitro-1H-pyrazol-1-yl)(o-tolyl)methanone | Drug Info | [22] | |||
| 14 | (4-nitro-1H-pyrazol-1-yl)(phenyl)methanone | Drug Info | [22] | |||
| 15 | 1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide | Drug Info | [22] | |||
| 16 | 1-guanidino-7-isoquinolinesulphonamide | Drug Info | [24] | |||
| 17 | 1-guanidino-N-phenyl-7-isoquinolinesulphonamide | Drug Info | [24] | |||
| 18 | 1-[4-(2-oxo-2-phenylethyl)phenyl]guanidine | Drug Info | [21] | |||
| 19 | 2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine | Drug Info | [25] | |||
| 20 | 2-Amino-5-Hydroxy-Benzimidazole | Drug Info | [26] | |||
| 21 | 2-nas-phe(3-am)-4-(2-guanidinoethyl)piperidine | Drug Info | [27] | |||
| 22 | 4-chloro-1-guanidino-7-isoquinolinesulphonamide | Drug Info | [24] | |||
| 23 | 4-iodobenzo[b]thiophene 2-carboxamidine | Drug Info | [28], [29] | |||
| 24 | 4-methoxy-N'-(2-phenylacetyl)benzohydrazide | Drug Info | [22] | |||
| 25 | 5-Methylsulfanyl-thiophene-2-carboxamidine | Drug Info | [29] | |||
| 26 | 6-(N-Phenylcarbamyl)-2-Naphthalenecarboxamidine | Drug Info | [26] | |||
| 27 | Benzamidine | Drug Info | [26] | |||
| 28 | CRA_10655 | Drug Info | [21] | |||
| 29 | CRA_8696 | Drug Info | [21] | |||
| 30 | Fucose | Drug Info | [26] | |||
| 31 | N-(1-Adamantyl)-N'-(4-Guanidinobenzyl)Urea | Drug Info | [26] | |||
| 32 | Recombinant human pro-urokinase | Drug Info | [1] | |||
| 33 | Thieno[2,3-B]Pyridine-2-Carboxamidine | Drug Info | [21] | |||
| 34 | UPA-targeted oncolytic Sendai virus | Drug Info | [1] | |||
| Activator | [+] 4 Activator drugs | + | ||||
| 1 | Amediplase | Drug Info | [3] | |||
| 2 | Saruplase | Drug Info | [5] | |||
| 3 | HTU-PA | Drug Info | [17] | |||
| 4 | ATN-658 | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Tranexamic acid | Ligand Info | |||||
| Structure Description | Tranexamic Acid is an Active Site Inhibitor of Urokinase Plasminogen Activator | PDB:6NMB | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [32] |
| PDB Sequence |
FQCGQIIGGE
20 FTTIENQPWF30 AAIYRRHRGG37C SVTYVCGGSL46 ISPCWVISAT56 HCFIDYPKKE 62A DYIVYLGRSR72 LNSNTQGEMK82 FEVENLILHK92 DYSADTLAHH100 NDIALLKIRS 110 KEGRCAQPSR116 TIQTICLPSM126 YNDPQFGTSC136 EITGFGKENS146 TDYLYPEQLK 156 MTVVKLISHR166 ECQQPHYYGS174 EVTTKMLCAA184 DPQWKTDSCQ192 GDSGGPLVCS 202 LQGRMTLTGI212 VSWGRGCALK222 DKPGVYTRVS232 HFLPWIRSHT242 K |
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| Ligand Name: L-alanine | Ligand Info | |||||
| Structure Description | Crystal structure of uPA in complex with upain-2-3-W3A | PDB:5WXP | ||||
| Method | X-ray diffraction | Resolution | 1.75 Å | Mutation | Yes | [33] |
| PDB Sequence |
IIGGEFTTIE
25 NQPWFAAIYR35 RHRGGSVTYV41 CGGSLISPCW51 VISATHCFID60A YPKKEDYIVY 67 LGRSRLNSNT77 QGEMKFEVEN87 LILHKDYSAD97 TLAHHNDIAL105 LKIRSKEGRC 111 AQPSRTIQTI121 ALPSMYNDPQ131 FGTSCEITGF141 GKEQSTDYLY151 PEQLKMTVVK 161 LISHRECQQP170A HYYGSEVTTK179 MLCAADPQWK187 TDSCQGDSGG197 PLVCSLQGRM 207 TLTGIVSWGR217 GCALKDKPGV227 YTRVSHFLPW237 IRSHTKEE
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| NF-kappa B signaling pathway | hsa04064 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Complement and coagulation cascades | hsa04610 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 9 | Degree centrality | 9.67E-04 | Betweenness centrality | 1.40E-04 |
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| Closeness centrality | 2.33E-01 | Radiality | 1.41E+01 | Clustering coefficient | 3.89E-01 |
| Neighborhood connectivity | 4.90E+01 | Topological coefficient | 1.57E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-regulating Transcription Factors | ||||||
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 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). | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | Emerging drugs in peripheral arterial disease. Expert Opin Emerg Drugs. 2006 Mar;11(1):75-90. | |||||
| REF 4 | Amediplase: CGP 42935, K2tu-PA, MEN 9036. BioDrugs. 2002;16(5):378-9. | |||||
| REF 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. | |||||
| REF 6 | 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. (Ligand id: 6497). | |||||
| REF 7 | 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. | |||||
| REF 8 | ClinicalTrials.gov (NCT00418275) Safety Study of a Recombinant Human Plasminogen Activator to Treat Acute Ischemic Stroke.. U.S. National Institutes of Health. | |||||
| REF 9 | 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. | |||||
| REF 10 | 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. (Ligand id: 6545). | |||||
| REF 11 | Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30. | |||||
| REF 12 | 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. (Ligand id: 6498). | |||||
| REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012176) | |||||
| REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009078) | |||||
| REF 15 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
| REF 16 | 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. | |||||
| REF 17 | Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells. J Biol Chem. 1986 Mar 25;261(9):4352-7. | |||||
| REF 18 | Topological localization of plasminogen activator inhibitor type 2. Cytometry. 2000 May 1;40(1):32-41. | |||||
| REF 19 | Inhibition 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 20 | Natural and synthetic inhibitors of the tumor-associated serine protease urokinase-type plasminogen activator. Adv Exp Med Biol. 2000;477:331-41. | |||||
| REF 21 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 22 | N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. J Med Chem. 2007 Oct 4;50(20):4928-38. | |||||
| REF 23 | 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. | |||||
| REF 24 | Selective urokinase-type plasminogen activator inhibitors. 4. 1-(7-sulfonamidoisoquinolinyl)guanidines. J Med Chem. 2007 May 17;50(10):2341-51. | |||||
| REF 25 | 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. | |||||
| REF 26 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 27 | Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. J Med Chem. 2006 Jul 13;49(14):4116-26. | |||||
| REF 28 | Structural 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 29 | 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. | |||||
| REF 30 | 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. | |||||
| REF 31 | Angiostatic activity of synthetic inhibitors of urokinase type plasminogen activator. Oncol Rep. 1999 May-Jun;6(3):523-6. | |||||
| REF 32 | Tranexamic acid is an active site inhibitor of urokinase plasminogen activator. Blood Adv. 2019 Mar 12;3(5):729-733. | |||||
| REF 33 | Cleavage of peptidic inhibitors by target protease is caused by peptide conformational transition. Biochim Biophys Acta Gen Subj. 2018 Sep;1862(9):2017-2023. | |||||
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