Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT38RM1)

DTT Name Glycoprotein IIb/IIIa receptor (GPIIb/IIIa)
Synonyms Platelet membrane glycoprotein IIb; Platelet membrane glycoprotein IIIa; GP
Gene Name ITGA2B; ITGB3
DTT Type
Successful target
 [1]
Related Disease
Acquired hypermelanosis [ICD-11: ED60]
Angina pectoris [ICD-11: BA40]
Myocardial infarction [ICD-11: BA41-BA43]
UniProt ID
ITA2B_HUMAN ; ITB3_HUMAN
TTD ID
T50688
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MARALCPLQALWLLEWVLLLLGPCAAPPAWALNLDPVQLTFYAGPNGSQFGFSLDFHKDS
HGRVAIVVGAPRTLGPSQEETGGVFLCPWRAEGGQCPSLLFDLRDETRNVGSQTLQTFKA
RQGLGASVVSWSDVIVACAPWQHWNVLEKTEEAEKTPVGSCFLAQPESGRRAEYSPCRGN
TLSRIYVENDFSWDKRYCEAGFSSVVTQAGELVLGAPGGYYFLGLLAQAPVADIFSSYRP
GILLWHVSSQSLSFDSSNPEYFDGYWGYSVAVGEFDGDLNTTEYVVGAPTWSWTLGAVEI
LDSYYQRLHRLRGEQMASYFGHSVAVTDVNGDGRHDLLVGAPLYMESRADRKLAEVGRVY
LFLQPRGPHALGAPSLLLTGTQLYGRFGSAIAPLGDLDRDGYNDIAVAAPYGGPSGRGQV
LVFLGQSEGLRSRPSQVLDSPFPTGSAFGFSLRGAVDIDDNGYPDLIVGAYGANQVAVYR
AQPVVKASVQLLVQDSLNPAVKSCVLPQTKTPVSCFNIQMCVGATGHNIPQKLSLNAELQ
LDRQKPRQGRRVLLLGSQQAGTTLNLDLGGKHSPICHTTMAFLRDEADFRDKLSPIVLSL
NVSLPPTEAGMAPAVVLHGDTHVQEQTRIVLDCGEDDVCVPQLQLTASVTGSPLLVGADN
VLELQMDAANEGEGAYEAELAVHLPQGAHYMRALSNVEGFERLICNQKKENETRVVLCEL
GNPMKKNAQIGIAMLVSVGNLEEAGESVSFQLQIRSKNSQNPNSKIVLLDVPVRAEAQVE
LRGNSFPASLVVAAEEGEREQNSLDSWGPKVEHTYELHNNGPGTVNGLHLSIHLPGQSQP
SDLLYILDIQPQGGLQCFPQPPVNPLKVDWGLPIPSPSPIHPAHHKRDRRQIFLPEPEQP
SRLQDPVLVSCDSAPCTVVQCDLQEMARGQRAMVTVLAFLWLPSLYQRPLDQFVLQSHAW
FNVSSLPYAVPPLSLPRGEAQVWTQLLRALEERAIPIWWVLVGVLGGLLLLTILVLAMWK
VGFFKRNRPPLEEDDEEGE
Function
Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha- IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface.
KEGG Pathway
Rap1 signaling pathway (hsa04015 )
PI3K-Akt signaling pathway (hsa04151 )
Focal adhesion (hsa04510 )
ECM-receptor interaction (hsa04512 )
Platelet activation (hsa04611 )
Neutrophil extracellular trap formation (hsa04613 )
Hematopoietic cell lineage (hsa04640 )
Regulation of actin cytoskeleton (hsa04810 )
Human papillomavirus infection (hsa05165 )
Pathways in cancer (hsa05200 )
Small cell lung cancer (hsa05222 )
Hypertrophic cardiomyopathy (hsa05410 )
Arrhythmogenic right ventricular cardiomyopathy (hsa05412 )
Dilated cardiomyopathy (hsa05414 )
Fluid shear stress and atherosclerosis (hsa05418 )
Reactome Pathway
Elastic fibre formation (R-HSA-1566948 )
PECAM1 interactions (R-HSA-210990 )
Molecules associated with elastic fibres (R-HSA-2129379 )
Integrin cell surface interactions (R-HSA-216083 )
Syndecan interactions (R-HSA-3000170 )
ECM proteoglycans (R-HSA-3000178 )
Integrin alphaIIb beta3 signaling (R-HSA-354192 )
GRB2 (R-HSA-354194 )
p130Cas linkage to MAPK signaling for integrins (R-HSA-372708 )
VEGFA-VEGFR2 Pathway (R-HSA-4420097 )
MAP2K and MAPK activation (R-HSA-5674135 )
Platelet degranulation (R-HSA-114608 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
4 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Abciximab DMJO6GV Angina pectoris BA40 Approved [2]
Eptifibatide DMQXTJS Acute cardiac ischemic events BA40.Z Approved [3]
Hydroquinone DM6AVR4 Melasma ED60.1 Approved [1]
Tirofiban DMQG17S Acute coronary syndrome BA41 Approved [2]
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6 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
DMP-444 DMO7BQS Coronary artery disease BA80 Phase 3 [4]
99mTc-rBitistatin DMFAMNH Embolism JB42 Phase 1/2 [5]
AjvW2 DM6PN4H Thrombosis DB61-GB90 Phase 1 [6]
Lefradafiban DMKZVLH Angina pectoris BA40 Phase 1 [7]
RGD-891 DMVJMF1 Thrombosis DB61-GB90 Phase 1 [8]
SDZ-GPI-562 DMU9ZGN Thrombosis DB61-GB90 Phase 1 [9]
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⏷ Show the Full List of 6 Clinical Trial Drug(s)
28 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
LAMIFIBAN DMHR1A7 Angina pectoris BA40 Discontinued in Phase 3 [10]
LOTRAFIBAN DMHE804 Cardiovascular disease BA00-BE2Z Discontinued in Phase 3 [11]
ORBOFIBAN DMEDLXJ Angina pectoris BA40 Discontinued in Phase 3 [12]
SIBRAFIBAN DMZU1TV Angina pectoris BA40 Discontinued in Phase 3 [13]
XEMILOFIBAN DMBRYT8 Cardiovascular disease BA00-BE2Z Discontinued in Phase 3 [14], [15]
Cromafiban DMZLIUQ Coronary artery disease BA80 Discontinued in Phase 2 [16]
ELAROFIBAN DM7TM91 Thrombosis DB61-GB90 Discontinued in Phase 2 [17]
FK-633 DMQ3O4C Artery stenosis BD52 Discontinued in Phase 2 [18]
Gantofiban DMHAM2J Arteriosclerosis BD40 Discontinued in Phase 2 [19]
MK-852 DMBJLZG Thrombosis DB61-GB90 Discontinued in Phase 2 [16]
SR-121787 DMCEQKG Thrombosis DB61-GB90 Discontinued in Phase 2 [20], [21]
YM-337 DMCZIGQ Angiogenesis disorder BE2Z Discontinued in Phase 2 [22]
ZD-2486 DMLFNMB Angina pectoris BA40 Discontinued in Phase 2 [16]
DMP-728 DMCK7LM Thrombosis DB61-GB90 Discontinued in Phase 1 [23]
FR-158999 DM5FW8Y Thrombosis DB61-GB90 Discontinued in Phase 1 [24], [25]
L-734217 DMSB0J8 Thrombosis DB61-GB90 Discontinued in Phase 1 [26]
ME-3277 DMUMSFR Thrombosis DB61-GB90 Discontinued in Phase 1 [27]
SC-52012 DMFC19E Thrombosis DB61-GB90 Discontinued in Phase 1 [28]
TAK-029 DMN02XD Thrombosis DB61-GB90 Discontinued in Phase 1 [29]
TP-9201 DMCV2KQ Thrombosis DB61-GB90 Discontinued in Phase 1 [30]
BIBU-251 DMMNI5K Thrombosis DB61-GB90 Terminated [31]
Fradafiban DMN4E5H Thrombosis DB61-GB90 Terminated [32]
GR-144053 DMN8TH1 Thrombosis DB61-GB90 Terminated [33], [34]
GR-233548 DMHM0EU Thrombosis DB61-GB90 Terminated [2]
L-703014 DM47MKE Thrombosis DB61-GB90 Terminated [35]
SB-208651 DMJD15H Thrombosis DB61-GB90 Terminated [36], [37]
SC-49992 DMY7KHW Arterial thrombosis DB61-DD30 Terminated [38]
SKF-106760 DM7QPYK Thrombosis DB61-GB90 Terminated [2]
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⏷ Show the Full List of 28 Discontinued Drug(s)
3 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
RGD DMFASRB Discovery agent N.A. Investigative [39]
RGD-039 DM0O9VG Thrombosis DB61-GB90 Investigative [40], [8]
XV454 DML1K07 Discovery agent N.A. Investigative [41]
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Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Coronary artery disease BA80-BA8Z Peripheral blood 7.83E-01 -0.11 -0.45
Coronary artery disease BA80-BA8Z Peripheral blood 8.97E-01 0.1 0.39
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References

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2 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
3 Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. J Biol Chem. 1991 May 25;266(15):9359-62.
4 Evaluation of Tc-99m-labeled glycoprotein IIb/IIIa receptor antagonist DMP444 SPECT in patients with infective endocarditis. Clin Nucl Med. 2003 Jun;28(6):480-4.
5 Platelet binding and biodistribution of [99mTc]rBitistatin in animal species and humans. Nucl Med Biol. 2007 Oct;34(7):855-63.
6 Novel approaches to the treatment of thrombosis. Trends Pharmacol Sci. 2002 Jan;23(1):25-32.
7 Pharmacodynamics and safety of lefradafiban, an oral platelet glycoprotein IIb/IIIa receptor antagonist, in patients with stable coronary artery disease undergoing elective angioplasty. Heart. 2001 Apr;85(4):444-50.
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13 Pharmacokinetics and pharmacodynamics of sibrafiban, an orally administered GP IIb/IIIa antagonist, following coadministration of aspirin and heparin. J Clin Pharmacol. 2000 May;40(5):488-95.
14 Glycoprotein IIb/IIIa receptor number and occupancy during chronic administration of an oral antagonist. J Pharmacol Exp Ther. 2000 Nov;295(2):670-6.
15 Acute thrombocytopenia in patients treated with the oral glycoprotein IIb/IIIa inhibitors xemilofiban and orbofiban: evidence for an immune etiology. Thromb Haemost. 2002 Dec;88(6):892-7.
16 Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
17 1,2,4-triazolo[3,4-a]pyridine as a novel, constrained template for fibrinogen receptor (GPIIb/IIIa) antagonists. Bioorg Med Chem Lett. 2001 Oct 8;11(19):2619-22.
18 Efficacy of FK633, an ultra-short acting glycoprotein IIb/IIIa antagonist on platelet preservation during and after cardiopulmonary bypass. Eur J Cardiothorac Surg. 2004 Aug;26(2):289-93.
19 Enantioseparation of gantofiban precursors on chiral stationary phases of the poly-(N-acryloyl amino acid derivative)-type. J Pharm Biomed Anal. 2002 Jan 15;27(3-4):627-37.
20 Prevention of thrombosis and enhancement of thrombolysis in rabbits by SR 121787, a glycoprotein II/III antagonist. J Pharmacol Exp Ther. 1998 Aug;286(2):670-5.
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23 Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist. Circulation. 1994 Jan;89(1):3-12.
24 QSAR study of the peptidic fibrinogen inhibitors FK633, FR158999 and related derivatives, using a novel and useful hydrophobic descriptor (logPmw). Bioorganic & Medicinal Chemistry Letters Volume 8, Issue 18, 22 September 1998, Pages 2483-2488.
25 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
26 Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217. J Pharmacol Exp Ther. 1996 Jul;278(1):62-73.
27 ME3277, a GPIIb/IIIa antagonist reduces cerebral infarction without enhancing intracranial hemorrhage in photothrombotic occlusion of rabbit middle cerebral artery. J Cereb Blood Flow Metab. 2000 Jun;20(6):988-97.
28 Characterization of Binding of an RGD Mimetic, [(3)H]-SC-52012, to Platelet GPIIb/IIIa. Platelets. 1995;6(5):288-95.
29 Platelet protective effect of TAK-029, a novel glycoprotein IIb/IIIa antagonist: an in vitro study. Artif Organs. 1998 Apr;22(4):348-52.
30 TP-9201, a glycoprotein IIb/IIIa platelet receptor antagonist, prevents rethrombosis after successful arterial thrombolysis in the dog. Stroke. 1997 Sep;28(9):1789-96.
31 CN patent application no. 101312747, Anticoagulant antithrombotic dual inhibitors comprising a biotin label.
32 Profound and sustained inhibition of platelet aggregation by Fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, Lefradafiban, in men. Circulation. 1997Aug 19;96(4):1130-8.
33 GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in ... Br J Pharmacol. 1997 Nov;122(6):1099-104.
34 Effect of GR144053, a fibrinogen-receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tPA in the injured carotid a... J Cardiovasc Pharmacol. 1998 Aug;32(2):191-7.
35 Pharmacokinetics and pharmacodynamics of L-703,014, a potent fibrinogen receptor antagonist, after intravenous and oral administration in the dog. Pharm Res. 1994 Mar;11(3):426-31.
36 Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist. Bioorg Med Chem. 1994 Sep;2(9):897-908.
37 Chemical approaches to improve the oral bioavailability of peptidergic molecules.J Pharm Pharmacol.1996 Feb;48(2):119-35.
38 SC-49992--a potent and specific inhibitor of platelet aggregation. Thromb Res. 1994 Jun 1;74(5):523-35.
39 AlphaIIbbeta3 and its antagonism at the new millennium. Thromb Haemost. 2001 Jul;86(1):34-40.
40 Pharmacokinetics and concentration-effect analysis of intravenous RGD891, a platelet GPIIb/IIIa antagonist, using mixed-effects modeling (NONMEM). J Clin Pharmacol. 2000 Oct;40(10):1129-40.
41 Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454. Thromb Haemost. 2003 Sep;90(3):549-54.