Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTP86E2)

• DTT Name: Plasminogen (PLG)
• Synonyms: Plasmin
• Gene Name: PLG
• DTT Type: Successful target; [1]
• BioChemical Class: Peptidase
• UniProt ID: PLMN_HUMAN
• TTD ID: T89034
• EC Number: EC 3.4.21.7
• Sequence:
  MEHKEVVLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFT
  CRAFQYHSKEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKN
  GITCQKWSSTSPHRPRFSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILE
  CEEECMHCSGENYDGKISKTMSGLECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRE
  LRPWCFTTDPNKRWELCDIPRCTTPPPSSGPTYQCLKGTGENYRGNVAVTVSGHTCQHWS
  AQTPHTHNRTPENFPCKNLDENYCRNPDGKRAPWCHTTNSQVRWEYCKIPSCDSSPVSTE
  QLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKKCQSWSSMTPHRHQKTPENYPNAG
  LTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVVLLPDVETPSEED
  CMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDGDVGG
  PWCYTTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRT
  RFGMHFCGGTLISPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLE
  PTRKDIALLKLSSPAVITDKVIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQ
  LPVIENKVCNRYEFLNGRVQSTELCAGHLAGGTDSCQGDSGGPLVCFEKDKYILQGVTSW
  GLGCARPNKPGVYVRVSRFVTWIEGVMRNN
• Function: In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells. Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Complement and coagulation cascades (hsa04610)
  Staphylococcus aureus infection (hsa05150)
  Influenza A (hsa05164)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Dissolution of Fibrin Clot (R-HSA-75205)
  Platelet degranulation (R-HSA-114608)
• BioCyc Pathway: MetaCyc:HS04553-MON

Molecular Interaction Atlas (MIA) of This DTT

8 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alteplase	DMRJ3YX	Acute myocardial infarction	BA41	Approved	[2]
Aminocaproic Acid	DMFGND4	Bleeding disorder	GA20-GA21	Approved	[3]
Anistreplase	DM6Q4B0	Acute coronary syndrome	BA41	Approved	[4]
Ranolazine	DM0C9IL	Acute coronary syndrome	BA41	Approved	[5]
Reteplase	DML0D1P	Heart attack	BA41	Approved	[6]
Streptokinase	DM5JQ0D	Pulmonary embolism	BB00	Approved	[7]
Tenecteplase	DMJYN25	Acute myocardial infarction	BA41	Approved	[2]
Tranexamic Acid	DMFI8A7	Excessive bleeding	GA30.02	Approved	[1]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Desmoteplase	DMDLU4Z	Ischemic stroke	8B11.5Z	Phase 3	[8]
MELAGATRAN	DM4W8RE	N. A.	N. A.	Phase 3	[9]
Plasminogen	DM0EFQS	Alzheimer disease	8A20	Phase 2/3	[10]
BIIB131	DMDG3AD	Acute ischemic stroke	8B11	Phase 2	[11]
RetinoStat	DMVXZJ4	Macular degeneration	9B78.3	Phase 2	[12]
Troplasminogen alfa	DMR8Y4F	Myocardial infarction	BA41-BA43	Phase 2	[13]
bis-triazole derivative 10	DMN2EI1	Otitis media	AA80-AB0Z	Clinical trial	[14]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-(2-Oxo-2-p-tolyl-ethyl)-1H-indole-2,3-dione	DM69T3A	Discovery agent	N.A.	Investigative	[15]
1-(3,3-Dimethyl-2-oxo-butyl)-1H-indole-2,3-dione	DMNZYWR	Discovery agent	N.A.	Investigative	[15]
1-guanidino-7-isoquinolinesulphonamide	DM48TIN	Discovery agent	N.A.	Investigative	[16]
1-guanidino-N-phenyl-7-isoquinolinesulphonamide	DMTF1HL	Discovery agent	N.A.	Investigative	[16]
2-(2-Hydroxy-phenyl)-1H-indole-5-carboxamidine	DM3UMYD	Discovery agent	N.A.	Investigative	[17]
Bicine	DMTRDPI	Discovery agent	N.A.	Investigative	[18]
Grassystatin a	DM1PWX2	Discovery agent	N.A.	Investigative	[19]
M5	DM3IX2E	Cerebrovascular ischaemia	8B1Z	Investigative	[5]
N-(4-Chloro-7-p-tolyl-isoquinolin-1-yl)-guanidine	DMNO46U	Discovery agent	N.A.	Investigative	[20]
SMTP-0	DM9SF48	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]
Textilinin	DMHBMJZ	Bleeding disorder	GA20-GA21	Investigative	[5]
XP-21510	DMGOMYN	Menorrhagia	GA20.50	Investigative	[5]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	8.61E-01	-0.01	-0.09

References

• [1] Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation. J Thromb Haemost. 2007 Oct;5(10):2113-8.
• [2] Thrombolytic therapies: the current state of affairs. J Endovasc Ther. 2005 Apr;12(2):224-32.
• [3] The blockage of the high-affinity lysine binding sites of plasminogen by EACA significantly inhibits prourokinase-induced plasminogen activation. Biochim Biophys Acta. 2002 Apr 29;1596(2):182-92.
• [4] Evaluation of thrombolytic agents. Drugs. 1997;54 Suppl 3:11-6; discussion 16-7.
• [5] Tranexamic acid in trauma: how should we use it. J Trauma Acute Care Surg. 2013 Jun;74(6):1575-86.
• [6] Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):212-23.
• [7] Acute anuric renal failure with streptokinase therapy in a patient with acute venous thromboembolic disease and the review of renal side effects of streptokinase. Tuberk Toraks. 2008;56(4):456-61.
• [8] Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke. 2003 Feb;34(2):537-43.
• [9] Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety. Bioorg Med Chem Lett. 2006 May 15;16(10):2641-7.
• [10] Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005 Apr;93(4):647-54.
• [11] Clinical pipeline report, company report or official report of Biogen
• [12] Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat( ), for age-related macular degeneration. Hum Gene Ther. 2012 Sep;23(9):980-91.
• [13] V-10153 (Vernalis). Curr Opin Investig Drugs. 2005 Sep;6(9):951-5.
• [14] A new strategy for the development of highly potent and selective plasmin inhibitors. J Med Chem. 2012 Feb 9;55(3):1171-80.
• [15] Parallel synthesis of isatin-based serine protease inhibitors. Bioorg Med Chem Lett. 2000 Nov 20;10(22):2501-4.
• [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.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. J Med Chem. 2009 Sep 24;52(18):5732-47.
• [20] Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30.