Target Information

Target General Information

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Target ID

T23355 (Former ID: TTDR01362)

Target Name

ITGB3 messenger RNA (ITGB3 mRNA)

Synonyms

Platelet membrane glycoprotein IIIa (mRNA); Integrin beta-3 (mRNA); GPIIIa (mRNA); GP3A (mRNA); CD61 (mRNA)

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Gene Name

ITGB3

Target Type

Discontinued target

[1]

Disease

[+] 2 Target-related Diseases

Cardiovascular disease [ICD-11: BA00-BE2Z]

Chronic arterial occlusive disease [ICD-11: BD4Z]

Function

Integrin alpha-IIb/beta-3 (ITGA2B:ITGB3) is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 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 surface. Fibrinogen binding enhances SELP expression in activated platelets. ITGAV:ITGB3 binds to fractalkine (CX3CL1) and acts as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling. ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling. ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling. ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling. ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling. ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling. ITGAV:ITGB3 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1. ITGAV:ITGB3 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1. Integrin alpha-V/beta-3 (ITGAV:ITGB3) is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor.

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BioChemical Class

mRNA target

UniProt ID

ITB3_HUMAN

Sequence

MRARPRPRPLWATVLALGALAGVGVGGPNICTTRGVSSCQQCLAVSPMCAWCSDEALPLG
SPRCDLKENLLKDNCAPESIEFPVSEARVLEDRPLSDKGSGDSSQVTQVSPQRIALRLRP
DDSKNFSIQVRQVEDYPVDIYYLMDLSYSMKDDLWSIQNLGTKLATQMRKLTSNLRIGFG
AFVDKPVSPYMYISPPEALENPCYDMKTTCLPMFGYKHVLTLTDQVTRFNEEVKKQSVSR
NRDAPEGGFDAIMQATVCDEKIGWRNDASHLLVFTTDAKTHIALDGRLAGIVQPNDGQCH
VGSDNHYSASTTMDYPSLGLMTEKLSQKNINLIFAVTENVVNLYQNYSELIPGTTVGVLS
MDSSNVLQLIVDAYGKIRSKVELEVRDLPEELSLSFNATCLNNEVIPGLKSCMGLKIGDT
VSFSIEAKVRGCPQEKEKSFTIKPVGFKDSLIVQVTFDCDCACQAQAEPNSHRCNNGNGT
FECGVCRCGPGWLGSQCECSEEDYRPSQQDECSPREGQPVCSQRGECLCGQCVCHSSDFG
KITGKYCECDDFSCVRYKGEMCSGHGQCSCGDCLCDSDWTGYYCNCTTRTDTCMSSNGLL
CSGRGKCECGSCVCIQPGSYGDTCEKCPTCPDACTFKKECVECKKFDRGALHDENTCNRY
CRDEIESVKELKDTGKDAVNCTYKNEDDCVVRFQYYEDSSGKSILYVVEEPECPKGPDIL
VVLLSVMGAILLIGLAALLIWKLLITIHDRKEFAKFEEERARAKWDTANNPLYKEATSTF
TNITYRGT

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Drugs and Modes of Action

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Discontinued Drug(s)

[+] 1 Discontinued Drugs

XEMILOFIBAN

Drug Info

Discontinued in Phase 3

Peripheral vascular disease

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 75 Inhibitor drugs

XEMILOFIBAN

Drug Info

[1]

DMP-802

Drug Info

[3]

DMP-757

Drug Info

[4]

L-709780

Drug Info

[5]

L-738167

Drug Info

[3]

Ro-43-5054

Drug Info

[3]

Ro-43-8857

Drug Info

[3]

SB-223245

Drug Info

[6]

SC-47643

Drug Info

[7]

SKF-107260

Drug Info

[8]

3-(3-(benzamido)-5-nitrobenzamido)propanoic acid

Drug Info

[9]

3-(3-(carbamoyl)benzamido)-3-phenylpropanoic acid

Drug Info

[9]

3-(3-(carbamoyl)benzamido)propanoic acid

Drug Info

[9]

Ac-Asp-Arg-Leu-Asp-Ser-OH

Drug Info

[10]

AcDRGDS

Drug Info

[11]

C(-GRGDfL-)

Drug Info

[12]

C(Arg-Gly-Asp-D-Phe-Val)

Drug Info

[13]

C(RGDfF)

Drug Info

[14]

C(RGDfMeF)

Drug Info

[14]

C-[-Arg-Gly-Asp-Acpca30-]

Drug Info

[15]

C-[-Arg-Gly-Asp-Acpca31-]

Drug Info

[15]

C-[-Arg-Gly-Asp-Acpca32-]

Drug Info

[15]

C-[-Arg-Gly-Asp-Acpca33-]

Drug Info

[15]

Cyclo(RGDfV) (control)

Drug Info

[16]

Cyclo-[-Arg-Gly-Asp-Amp21-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp22-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp23-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp24-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp25-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp26-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp27-]

Drug Info

[17]

Cyclo-[-Arg-Gly-Asp-Amp28-]

Drug Info

[17]

CYCLORGDFV

Drug Info

[18]

Cyclo[RGDfK(cypate)]

Drug Info

[16]

Cypate-[(RGD)2-NH2]1

Drug Info

[16]

Cypate-[(RGD)2-NH2]2

Drug Info

[16]

Cypate-[(RGD)3-NH2]1

Drug Info

[16]

Cypate-[(RGD)3-NH2]2

Drug Info

[16]

Cypate-[(RGD)4-NH2]1

Drug Info

[16]

Cypate-[(RGD)4-NH2]2

Drug Info

[16]

C[-Arg-Gly-Asp-Acpca19-]

Drug Info

[15]

C[-Arg-Gly-Asp-Acpca20-]

Drug Info

[15]

C[-Arg-Gly-Asp-Acpca21-]

Drug Info

[15]

C[-Arg-Gly-Asp-Acpca22-]

Drug Info

[15]

C[-Arg-Gly-Asp-Acpca34-]

Drug Info

[15]

C[-Arg-Gly-Asp-Acpca35-]

Drug Info

[15]

C[-Arg-Gly-Asp-Acpca36-]

Drug Info

[15]

C[RGD-(R)-alpha-TfmfV]

Drug Info

[14]

C[RGD-(S)-alpha-TfmfV]

Drug Info

[14]

C[RGDf-(R)-alpha-TfmF]

Drug Info

[14]

C[RGDf-(R)-alpha-TfmV]

Drug Info

[14]

C[RGDf-(R)-N-Me-alpha-TfmF]

Drug Info

[14]

C[RGDf-(S)-alpha-TfmF]

Drug Info

[14]

C[RGDf-(S)-alpha-TfmV]

Drug Info

[14]

C[RGDf-(S)-N-Me-alpha-TfmF]

Drug Info

[14]

C[RGDf-(S,R)-alpha-Dfm-F]

Drug Info

[14]

E[c(RGDyK)]2

Drug Info

[19]

E[c(RGDyK)]2-PTX conjugate

Drug Info

[19]

Gly-Arg-Gly-Asp-Ser

Drug Info

[20]

Gly-Arg-Gly-Asp-Ser-Pro-Lys

Drug Info

[21]

ISONIPECOTAMIDE

Drug Info

[23]

L-734115

Drug Info

[3]

L-739758

Drug Info

[3]

L-746233

Drug Info

[3]

L-750034

Drug Info

[24]

L-756568

Drug Info

[3]

L-767679

Drug Info

[3]

N-(3,5-dichlorophenyl)imidodicarbonimidic diamide

Drug Info

[25]

RGDechi

Drug Info

[13]

ROXIFIBAN

Drug Info

[3]

RWJ-53419

Drug Info

[26]

SB-207043

Drug Info

[8]

SB-265123

Drug Info

[27]

SC-54701A

Drug Info

[28]

ST-1646

Drug Info

[17]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 15 KEGG Pathways	+
1	Rap1 signaling pathway
2	Phagosome
3	PI3K-Akt signaling pathway
4	Osteoclast differentiation
5	Focal adhesion
6	ECM-receptor interaction
7	Platelet activation
8	Hematopoietic cell lineage
9	Regulation of actin cytoskeleton
10	Thyroid hormone signaling pathway
11	Proteoglycans in cancer
12	MicroRNAs in cancer
13	Hypertrophic cardiomyopathy (HCM)
14	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
15	Dilated cardiomyopathy
NetPath Pathway	[+] 1 NetPath Pathways	+
1	Leptin Signaling Pathway
PID Pathway	[+] 14 PID Pathways	+
1	IL4-mediated signaling events
2	Integrin family cell surface interactions
3	Signaling events mediated by PTP1B
4	Beta3 integrin cell surface interactions
5	S1P3 pathway
6	Osteopontin-mediated events
7	Nectin adhesion pathway
8	Arf6 signaling events
9	S1P1 pathway
10	Integrins in angiogenesis
11	Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling
12	PDGFR-beta signaling pathway
13	Signaling events mediated by VEGFR1 and VEGFR2
14	Ephrin B reverse signaling
Reactome	[+] 12 Reactome Pathways	+
1	Platelet degranulation
2	Elastic fibre formation
3	PECAM1 interactions
4	Molecules associated with elastic fibres
5	Integrin cell surface interactions
6	Syndecan interactions
7	ECM proteoglycans
8	Integrin alphaIIb beta3 signaling
9	GRB2:SOS provides linkage to MAPK signaling for Integrins
10	p130Cas linkage to MAPK signaling for integrins
11	VEGFA-VEGFR2 Pathway
12	MAP2K and MAPK activation
WikiPathways	[+] 19 WikiPathways	+
1	Monoamine Transport
2	TGF beta Signaling Pathway
3	Osteoblast Signaling
4	Focal Adhesion
5	Hematopoietic Stem Cell Differentiation
6	Human Complement System
7	Syndecan interactions
8	Extracellular matrix organization
9	Elastic fibre formation
10	Primary Focal Segmental Glomerulosclerosis FSGS
11	Arrhythmogenic Right Ventricular Cardiomyopathy
12	Integrin-mediated Cell Adhesion
13	L1CAM interactions
14	Integrin cell surface interactions
15	Integrin alphaIIb beta3 signaling
16	Cell surface interactions at the vascular wall
17	Serotonin Transporter Activity
18	Osteopontin Signaling
19	Osteoclast Signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Potent, orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure-activity studies leading to the discovery of RWJ-53308. J Med Chem. 1999 Dec 16;42(25):5254-65.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004434)

REF 3

Platelet glycoprotein IIb-IIIa antagonists as prototypical integrin blockers: novel parenteral and potential oral antithrombotic agents. J Med Chem. 2000 Sep 21;43(19):3453-73.

REF 4

Synthesis and antiplatelet activity of DMP 757 analogs, Bioorg. Med. Chem. Lett. 5(18):2097-2100 (1995).

REF 5

Non-peptide fibrinogen receptor antagonists. 3. design and discovery of a centrally constrained inhibitorc, Bioorg. Med. Chem. Lett. 4(15):1835-1840 (1994).

REF 6

Discovery of an imidazopyridine-containing 1,4-benzodiazepine nonpeptide vitronectin receptor (alpha v beta 3) antagonist with efficacy in a resten... Bioorg Med Chem Lett. 1998 Nov 17;8(22):3171-6.

REF 7

Novel thiazole-based heterocycles as selective inhibitors of fibrinogen-mediated platelet aggregation. J Med Chem. 1995 Jan 6;38(1):34-41.

REF 8

Preparation and Properties of a fibrinogen receptor antagonist containing the Arg-Gly-Asp sequence and nitroxide radicals, Bioorg. Med. Chem. Lett. 3(6):1179-1184 (1993).

REF 9

Derivatives of 7-amino-1,2,3,4-tetrahydroisoquinoline and isophthalic acids as novel fibrinogen receptor antagonists. Bioorg Med Chem Lett. 2006 Oct 15;16(20):5294-7.

REF 10

Synthesis and biological evaluation of non-peptide alpha(v)beta(3)/alpha(5)beta(1) integrin dual antagonists containing 5,6-dihydropyridin-2-one sc... Bioorg Med Chem. 2007 Dec 1;15(23):7380-90.

REF 11

Inhibition of cancer cell adhesion by heterochiral Pro-containing RGD mimetics. Bioorg Med Chem Lett. 2007 Apr 15;17(8):2329-33.

REF 12

Multiple N-methylation by a designed approach enhances receptor selectivity. J Med Chem. 2007 Nov 29;50(24):5878-81.

REF 13

Novel and selective alpha(v)beta3 receptor peptide antagonist: design, synthesis, and biological behavior. J Med Chem. 2006 Jun 1;49(11):3416-20.

REF 14

Incorporation of the unusual C(alpha)-fluoroalkylamino acids into cyclopeptides: synthesis of arginine-glycine-aspartate (RGD) analogues and study ... J Med Chem. 2006 Mar 9;49(5):1808-17.

REF 15

Grafting aminocyclopentane carboxylic acids onto the RGD tripeptide sequence generates low nanomolar alphaVbeta3/alphaVbeta5 integrin dual binders. J Med Chem. 2005 Dec 1;48(24):7675-87.

REF 16

Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors. J Med Chem. 2006 Apr 6;49(7):2268-75.

REF 17

Discovery of subnanomolar arginine-glycine-aspartate-based alphaVbeta3/alphaVbeta5 integrin binders embedding 4-aminoproline residues. J Med Chem. 2008 Mar 27;51(6):1771-82.

REF 18

Antiangiogenic effect of dual/selective alpha(5)beta(1)/alpha(v)beta(3) integrin antagonists designed on partially modified retro-inverso cyclotetr... J Med Chem. 2010 Jan 14;53(1):106-18.

REF 19

Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery. J Med Chem. 2005 Feb 24;48(4):1098-106.

REF 20

alphavbeta3 Integrin-targeting Arg-Gly-Asp (RGD) peptidomimetics containing oligoethylene glycol (OEG) spacers. J Med Chem. 2009 Nov 26;52(22):7029-43.

REF 21

N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem. 1999 Aug 12;42(16):3033-40.

REF 22

US patent application no. 7,425,545, Modulation of C-reactive protein expression.

REF 23

Piperidine-containing beta-arylpropionic acids as potent antagonists of alphavbeta3/alphavbeta5 integrins. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5227-32.

REF 24

Molecular model of the alpha(IIb)beta(3) integrin. J Med Chem. 2003 Dec 4;46(25):5316-25.

REF 25

Emerging targets in osteoporosis disease modification. J Med Chem. 2010 Jun 10;53(11):4332-53.

REF 26

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.

REF 27

1,2,3,4-Tetrahydroquinoline-containing alphaVbeta3 integrin antagonists with enhanced oral bioavailability. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5937-41.

REF 28

Use of conformationally restricted benzamidines as arginine surrogates in the design of platelet GPIIb-IIIa receptor antagonists. J Med Chem. 1997 Aug 29;40(18):2843-57.

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