Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT1R2L)

• DTT Name: Integrin alpha-V (ITGAV)
• Synonyms: Vitronectin receptor subunit alpha; Vitronectin receptor alpha subunit; Vitronectin receptor; VTNR; VNRA; MSK8; CD51 antigen; CD51
• Gene Name: ITGAV
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Integrin
• UniProt ID: ITAV_HUMAN
• TTD ID: T67103
• Sequence:
  MAFPPRRRLRLGPRGLPLLLSGLLLPLCRAFNLDVDSPAEYSGPEGSYFGFAVDFFVPSA
  SSRMFLLVGAPKANTTQPGIVEGGQVLKCDWSSTRRCQPIEFDATGNRDYAKDDPLEFKS
  HQWFGASVRSKQDKILACAPLYHWRTEMKQEREPVGTCFLQDGTKTVEYAPCRSQDIDAD
  GQGFCQGGFSIDFTKADRVLLGGPGSFYWQGQLISDQVAEIVSKYDPNVYSIKYNNQLAT
  RTAQAIFDDSYLGYSVAVGDFNGDGIDDFVSGVPRAARTLGMVYIYDGKNMSSLYNFTGE
  QMAAYFGFSVAATDINGDDYADVFIGAPLFMDRGSDGKLQEVGQVSVSLQRASGDFQTTK
  LNGFEVFARFGSAIAPLGDLDQDGFNDIAIAAPYGGEDKKGIVYIFNGRSTGLNAVPSQI
  LEGQWAARSMPPSFGYSMKGATDIDKNGYPDLIVGAFGVDRAILYRARPVITVNAGLEVY
  PSILNQDNKTCSLPGTALKVSCFNVRFCLKADGKGVLPRKLNFQVELLLDKLKQKGAIRR
  ALFLYSRSPSHSKNMTISRGGLMQCEELIAYLRDESEFRDKLTPITIFMEYRLDYRTAAD
  TTGLQPILNQFTPANISRQAHILLDCGEDNVCKPKLEVSVDSDQKKIYIGDDNPLTLIVK
  AQNQGEGAYEAELIVSIPLQADFIGVVRNNEALARLSCAFKTENQTRQVVCDLGNPMKAG
  TQLLAGLRFSVHQQSEMDTSVKFDLQIQSSNLFDKVSPVVSHKVDLAVLAAVEIRGVSSP
  DHVFLPIPNWEHKENPETEEDVGPVVQHIYELRNNGPSSFSKAMLHLQWPYKYNNNTLLY
  ILHYDIDGPMNCTSDMEINPLRIKISSLQTTEKNDTVAGQGERDHLITKRDLALSEGDIH
  TLGCGVAQCLKIVCQVGRLDRGKSAILYVKSLLWTETFMNKENQNHSYSLKSSASFNVIE
  FPYKNLPIEDITNSTLVTTNVTWGIQPAPMPVPVWVIILAVLAGLLLLAVLVFVMYRMGF
  FKRVRPPQEEQEREQLQPHENGEGNSET
• Function: The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. ITGAV:ITGB3 binds to fractalkine (CX3CL1) and may act 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 and ITGAV:ITGB6 act as a receptor for fibrillin-1 (FBN1) and mediate R-G-D-dependent cell adhesion to FBN1. Integrin alpha-V/beta-6 or alpha-V/beta-8 (ITGAV:ITGB6 or ITGAV:ITGB8) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation.
• KEGG Pathway:
  Phagosome (hsa04145)
  PI3K-Akt signaling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (CAMs) (hsa04514)
  Regulation of actin cytoskeleton (hsa04810)
  Thyroid hormone signaling pathway (hsa04919)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Small cell lung cancer (hsa05222)
  Hypertrophic cardiomyopathy (HCM) (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• 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)
  Laminin interactions (R-HSA-3000157)
  Syndecan interactions (R-HSA-3000170)
  ECM proteoglycans (R-HSA-3000178)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Cross-presentation of particulate exogenous antigens (phagosomes) (R-HSA-1236973)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Abituzumab	DMTCXSG	Colorectal cancer	2B91.Z	Phase 2	[1]
IMGN-388	DMSYB83	Solid tumour/cancer	2A00-2F9Z	Phase 1	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SB-223245	DM3JQCF	N. A.	N. A.	Terminated	[3]

56 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ac-Asp-Arg-Leu-Asp-Ser-OH	DMYHADT	Discovery agent	N.A.	Investigative	[4]
AcDRGDS	DM9MDBO	Discovery agent	N.A.	Investigative	[5]
C(-GRGDfL-)	DMTMJAI	Discovery agent	N.A.	Investigative	[6]
C(Arg-Gly-Asp-D-Phe-Val)	DMHNZGP	Discovery agent	N.A.	Investigative	[7]
C(RGDfF)	DMMBESU	Discovery agent	N.A.	Investigative	[8]
C(RGDfMeF)	DM8DU42	Discovery agent	N.A.	Investigative	[8]
C-[-Arg-Gly-Asp-Acpca30-]	DML0U8B	Discovery agent	N.A.	Investigative	[9]
C-[-Arg-Gly-Asp-Acpca31-]	DMKENFU	Discovery agent	N.A.	Investigative	[9]
C-[-Arg-Gly-Asp-Acpca32-]	DMVM7B2	Discovery agent	N.A.	Investigative	[9]
C-[-Arg-Gly-Asp-Acpca33-]	DMIBGWO	Discovery agent	N.A.	Investigative	[9]
Cyclo(RGDfV) (control)	DM3QVOB	Discovery agent	N.A.	Investigative	[10]
Cyclo-[-Arg-Gly-Asp-Amp21-]	DMVXPUB	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp22-]	DMBELJK	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp23-]	DMT29VJ	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp24-]	DM35ZLK	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp25-]	DMEIXUQ	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp26-]	DME5HRW	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp27-]	DMBNJZ0	Discovery agent	N.A.	Investigative	[11]
Cyclo-[-Arg-Gly-Asp-Amp28-]	DMJMHAV	Discovery agent	N.A.	Investigative	[11]
CYCLORGDFV	DMGZ0KM	N. A.	N. A.	Investigative	[12]
Cyclo[RGDfK(cypate)]	DMWYFLD	Discovery agent	N.A.	Investigative	[10]
Cypate-[(RGD)2-NH2]1	DMBTU7G	Discovery agent	N.A.	Investigative	[10]
Cypate-[(RGD)2-NH2]2	DMJNW9P	Discovery agent	N.A.	Investigative	[10]
Cypate-[(RGD)3-NH2]1	DMWINK5	Discovery agent	N.A.	Investigative	[10]
Cypate-[(RGD)3-NH2]2	DM1SAIX	Discovery agent	N.A.	Investigative	[10]
Cypate-[(RGD)4-NH2]1	DM3GLMP	Discovery agent	N.A.	Investigative	[10]
Cypate-[(RGD)4-NH2]2	DMR74OM	Discovery agent	N.A.	Investigative	[10]
C[-Arg-Gly-Asp-Acpca19-]	DMPOIDK	Discovery agent	N.A.	Investigative	[9]
C[-Arg-Gly-Asp-Acpca20-]	DMJVW1N	Discovery agent	N.A.	Investigative	[9]
C[-Arg-Gly-Asp-Acpca21-]	DMXCUDV	Discovery agent	N.A.	Investigative	[9]
C[-Arg-Gly-Asp-Acpca22-]	DM6DV90	Discovery agent	N.A.	Investigative	[9]
C[-Arg-Gly-Asp-Acpca34-]	DMKHSAV	Discovery agent	N.A.	Investigative	[9]
C[-Arg-Gly-Asp-Acpca35-]	DMQOY3J	Discovery agent	N.A.	Investigative	[9]
C[-Arg-Gly-Asp-Acpca36-]	DM7LCPW	Discovery agent	N.A.	Investigative	[9]
C[RGD-(R)-alpha-TfmfV]	DMF091Y	Discovery agent	N.A.	Investigative	[8]
C[RGD-(S)-alpha-TfmfV]	DMC9G2Y	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(3R)-Carboxymorpholine]	DM1DMR2	Discovery agent	N.A.	Investigative	[13]
C[RGDf-(3S)-Carboxymorpholine]	DM0ULZM	Discovery agent	N.A.	Investigative	[13]
C[RGDf-(R)-alpha-TfmF]	DMXA0JB	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(R)-alpha-TfmV]	DM8FGMA	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(R)-N-Me-alpha-TfmF]	DM4ZWOD	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(S)-alpha-TfmF]	DMCXJOL	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(S)-alpha-TfmV]	DMLRYXK	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(S)-N-Me-alpha-TfmF]	DMNS3HC	Discovery agent	N.A.	Investigative	[8]
C[RGDf-(S,R)-alpha-Dfm-F]	DMAILK8	Discovery agent	N.A.	Investigative	[8]
E[c(RGDyK)]2	DM76UJY	Discovery agent	N.A.	Investigative	[14]
E[c(RGDyK)]2-PTX conjugate	DMS1LZI	Discovery agent	N.A.	Investigative	[14]
G(D-Pen)-G-H-R-G-D-L-R-C-A	DMUC0F5	Discovery agent	N.A.	Investigative	[15]
Gly-Arg-Gly-Asp-Ser	DMACT8D	Discovery agent	N.A.	Investigative	[16]
Gly-Arg-Gly-Asp-Ser-Pro-Lys	DMGOIME	Discovery agent	N.A.	Investigative	[17]
ISONIPECOTAMIDE	DM5DKUY	Discovery agent	N.A.	Investigative	[18]
N-(3,5-dichlorophenyl)imidodicarbonimidic diamide	DMQ0LF2	Discovery agent	N.A.	Investigative	[19]
NAVPNLRGDLQVLAQKVART	DM3RP25	Discovery agent	N.A.	Investigative	[20]
RGDechi	DMX4JN6	Discovery agent	N.A.	Investigative	[7]
SB-265123	DM8UKH7	Discovery agent	N.A.	Investigative	[21]
ST-1646	DMR1G40	Discovery agent	N.A.	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	1.12E-02	0.71	1.79

References

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• [4] 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.
• [5] Inhibition of cancer cell adhesion by heterochiral Pro-containing RGD mimetics. Bioorg Med Chem Lett. 2007 Apr 15;17(8):2329-33.
• [6] Multiple N-methylation by a designed approach enhances receptor selectivity. J Med Chem. 2007 Nov 29;50(24):5878-81.
• [7] Novel and selective alpha(v)beta3 receptor peptide antagonist: design, synthesis, and biological behavior. J Med Chem. 2006 Jun 1;49(11):3416-20.
• [8] 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.
• [9] 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.
• [10] Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors. J Med Chem. 2006 Apr 6;49(7):2268-75.
• [11] 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.
• [12] 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.
• [13] Morpholine-based RGD-cyclopentapeptides as alphavbeta3/alphavbeta5 integrin ligands: role of configuration towards receptor binding affinity. Bioorg Med Chem. 2009 Feb 15;17(4):1542-9.
• [14] 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.
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• [16] alphavbeta3 Integrin-targeting Arg-Gly-Asp (RGD) peptidomimetics containing oligoethylene glycol (OEG) spacers. J Med Chem. 2009 Nov 26;52(22):7029-43.
• [17] 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.
• [18] Piperidine-containing beta-arylpropionic acids as potent antagonists of alphavbeta3/alphavbeta5 integrins. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5227-32.
• [19] Emerging targets in osteoporosis disease modification. J Med Chem. 2010 Jun 10;53(11):4332-53.
• [20] Structure-function analysis of Arg-Gly-Asp helix motifs in alpha v beta 6 integrin ligands. J Biol Chem. 2007 Mar 30;282(13):9657-65.
• [21] 1,2,3,4-Tetrahydroquinoline-containing alphaVbeta3 integrin antagonists with enhanced oral bioavailability. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5937-41.