Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT69TQN)

• DTT Name: Integrin alpha-V/beta-3 (ITGAV/B3)
• Synonyms: Integrin alphaVbeta3; Integrin alpha-v beta-3; Integrin alpha V beta 3; Alpha(v)beta(3) Integrin; Alpha v beta 3 integrin
• Gene Name: ITGAV-ITGB3
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Integrin
• UniProt ID: ITAV_HUMAN-ITB3_HUMAN
• TTD ID: T67363
• Sequence:
  MRARPRPRPLWATVLALGALAGVGVGGPNICTTRGVSSCQQCLAVSPMCAWCSDEALPLG
  SPRCDLKENLLKDNCAPESIEFPVSEARVLEDRPLSDKGSGDSSQVTQVSPQRIALRLRP
  DDSKNFSIQVRQVEDYPVDIYYLMDLSYSMKDDLWSIQNLGTKLATQMRKLTSNLRIGFG
  AFVDKPVSPYMYISPPEALENPCYDMKTTCLPMFGYKHVLTLTDQVTRFNEEVKKQSVSR
  NRDAPEGGFDAIMQATVCDEKIGWRNDASHLLVFTTDAKTHIALDGRLAGIVQPNDGQCH
  VGSDNHYSASTTMDYPSLGLMTEKLSQKNINLIFAVTENVVNLYQNYSELIPGTTVGVLS
  MDSSNVLQLIVDAYGKIRSKVELEVRDLPEELSLSFNATCLNNEVIPGLKSCMGLKIGDT
  VSFSIEAKVRGCPQEKEKSFTIKPVGFKDSLIVQVTFDCDCACQAQAEPNSHRCNNGNGT
  FECGVCRCGPGWLGSQCECSEEDYRPSQQDECSPREGQPVCSQRGECLCGQCVCHSSDFG
  KITGKYCECDDFSCVRYKGEMCSGHGQCSCGDCLCDSDWTGYYCNCTTRTDTCMSSNGLL
  CSGRGKCECGSCVCIQPGSYGDTCEKCPTCPDACTFKKECVECKKFDRGALHDENTCNRY
  CRDEIESVKELKDTGKDAVNCTYKNEDDCVVRFQYYEDSSGKSILYVVEEPECPKGPDIL
  VVLLSVMGAILLIGLAALLIWKLLITIHDRKEFAKFEEERARAKWDTANNPLYKEATSTF
  TNITYRGTMAFPPRRRLRLGPRGLPLLLSGLLLPLCRAFNLDVDSPAEYSGPEGSYFGFA
  VDFFVPSASSRMFLLVGAPKANTTQPGIVEGGQVLKCDWSSTRRCQPIEFDATGNRDYAK
  DDPLEFKSHQWFGASVRSKQDKILACAPLYHWRTEMKQEREPVGTCFLQDGTKTVEYAPC
  RSQDIDADGQGFCQGGFSIDFTKADRVLLGGPGSFYWQGQLISDQVAEIVSKYDPNVYSI
  KYNNQLATRTAQAIFDDSYLGYSVAVGDFNGDGIDDFVSGVPRAARTLGMVYIYDGKNMS
  SLYNFTGEQMAAYFGFSVAATDINGDDYADVFIGAPLFMDRGSDGKLQEVGQVSVSLQRA
  SGDFQTTKLNGFEVFARFGSAIAPLGDLDQDGFNDIAIAAPYGGEDKKGIVYIFNGRSTG
  LNAVPSQILEGQWAARSMPPSFGYSMKGATDIDKNGYPDLIVGAFGVDRAILYRARPVIT
  VNAGLEVYPSILNQDNKTCSLPGTALKVSCFNVRFCLKADGKGVLPRKLNFQVELLLDKL
  KQKGAIRRALFLYSRSPSHSKNMTISRGGLMQCEELIAYLRDESEFRDKLTPITIFMEYR
  LDYRTAADTTGLQPILNQFTPANISRQAHILLDCGEDNVCKPKLEVSVDSDQKKIYIGDD
  NPLTLIVKAQNQGEGAYEAELIVSIPLQADFIGVVRNNEALARLSCAFKTENQTRQVVCD
  LGNPMKAGTQLLAGLRFSVHQQSEMDTSVKFDLQIQSSNLFDKVSPVVSHKVDLAVLAAV
  EIRGVSSPDHVFLPIPNWEHKENPETEEDVGPVVQHIYELRNNGPSSFSKAMLHLQWPYK
  YNNNTLLYILHYDIDGPMNCTSDMEINPLRIKISSLQTTEKNDTVAGQGERDHLITKRDL
  ALSEGDIHTLGCGVAQCLKIVCQVGRLDRGKSAILYVKSLLWTETFMNKENQNHSYSLKS
  SASFNVIEFPYKNLPIEDITNSTLVTTNVTWGIQPAPMPVPVWVIILAVLAGLLLLAVLV
  FVMYRMGFFKRVRPPQEEQEREQLQPHENGEGNSET
• Function: Receptor for phagocytosis on macrophages or dendritic cells. In cancer and other diseases, its role in angiogenesis is directly responsible to providing blood supply to problematic overgrowths.
• KEGG Pathway:
  Phagosome (hsa04145)
  PI3K-Akt signaling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Hematopoietic cell lineage (hsa04640)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
  Pertussis (hsa05133)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Hypertrophic cardiomyopathy (HCM) (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (ARVC) (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Elastic fibre formation (R-HSA-1566948)
  Fibronectin matrix formation (R-HSA-1566977)
  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

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cilengitide	DMEAOZ0	Rheumatoid arthritis	FA20	Phase 3	[2]
ATN-161	DM4T9RS	Renal cell carcinoma	2C90	Phase 2	[1]
Fluciclatide F-18	DME01HT	Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]
Intetumumab	DMBXEG9	Prostate cancer	2C82.0	Phase 2	[4]
VLTS-589	DM4O17U	Peripheral vascular disease	BD4Z	Phase 2	[5]
SF0166	DM4NK3J	Diabetic macular edema	9B71.02	Phase 1/2	[6]
AMEP	DMFELMQ	Melanoma	2C30	Phase 1	[7]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Vitaxin	DMHCLVQ	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[8]
SB-267268	DMIBFAV	Osteoporosis	FB83.0	Discontinued in Phase 1	[9]
SB-273005	DMV7M1H	Osteoporosis	FB83.0	Discontinued in Phase 1	[10]
PS-388023	DM8P05S	Ocular disease	1F00.1Z	Terminated	[11]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
18F-SMIBR-K5	DM2VZMC	Solid tumour/cancer	2A00-2F9Z	Investigative	[12]
IS20I	DMXPMA6	Discovery agent	N.A.	Investigative	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	8.19E-02	-0.16	-0.46
Melanoma	2C82	Skin	3.31E-03	0.36	0.48
Osteoporosis	FA20	Bone marrow	1.44E-02	0.91	2.79
Rheumatoid arthritis	FA20	Synovial tissue	1.74E-01	0.09	0.14
Renal cancer	2C82	Kidney	5.75E-01	-0.24	-0.5

References

• [1] A non-RGD-based integrin binding peptide (ATN-161) blocks breast cancer growth and metastasis in vivo. Mol Cancer Ther. 2006 Sep;5(9):2271-80.
• [2] The integrin antagonist cilengitide activates alphaVbeta3, disrupts VE-cadherin localization at cell junctions and enhances permeability in endothelial cells.PLoS One.2009;4(2):e4449.
• [3] Use of a novel Arg-Gly-Asp radioligand, 18F-AH111585, to determine changes in tumor vascularity after antitumor therapy.J Nucl Med.2009 Jan;50(1):116-22.
• [4] A randomised, phase II study of intetumumab, an anti-alphav-integrin mAb, alone and with dacarbazine in stage IV melanoma. Br J Cancer. 2011 Jul 26;105(3):346-52.
• [5] AbbVie Licenses Phase II-Ready Antibody Programme to Receptos for Development in Eosinophilic Oesophagitis. 2013(4), Page 35.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Gene electrotransfer of plasmid AMEP, an integrin-targeted therapy, has antitumor and antiangiogenic action in murine B16 melanoma.Gene Ther.2015 Jul;22(7):578-90.
• [8] Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood. 2000 Jan 15;95(2):368-74.
• [9] SB-267268, a nonpeptidic antagonist of alpha(v)beta3 and alpha(v)beta5 integrins, reduces angiogenesis and VEGF expression in a mouse model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2006 Apr;47(4):1600-5.
• [10] Disease-modifying activity of SB 273005, an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthri... Arthritis Rheum. 2001 Jan;44(1):128-37.
• [11] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [12] Synthesis of [18F]RGD-K5 by catalyzed [3 + 2] cycloaddition for imaging integrin alphavbeta3 expression in vivo. Nucl Med Biol. 2013 Jul;40(5):710-6.
• [13] IS20I, a specific alphavbeta3 integrin inhibitor, reduces glioma growth in vivo. Neurosurgery. 2003 Jan;52(1):177-85; discussion 185-6.