Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Integrin beta-1 (ITGB1)
• Synonyms: VLA-4 subunit beta; MSK12; MDF2; Integrin VLA-4 beta subunit; Glycoprotein IIa; GPIIA; Fibronectin receptor subunit beta; Fibronectin receptor beta subunit; FNRB; CD29 antigen; CD29; Beta(1) integrin
• Gene Name: ITGB1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Integrin
• UniProt ID: ITB1_HUMAN
• TTD ID: T01851
• Sequence:
  MNLQPIFWIGLISSVCCVFAQTDENRCLKANAKSCGECIQAGPNCGWCTNSTFLQEGMPT
  SARCDDLEALKKKGCPPDDIENPRGSKDIKKNKNVTNRSKGTAEKLKPEDITQIQPQQLV
  LRLRSGEPQTFTLKFKRAEDYPIDLYYLMDLSYSMKDDLENVKSLGTDLMNEMRRITSDF
  RIGFGSFVEKTVMPYISTTPAKLRNPCTSEQNCTSPFSYKNVLSLTNKGEVFNELVGKQR
  ISGNLDSPEGGFDAIMQVAVCGSLIGWRNVTRLLVFSTDAGFHFAGDGKLGGIVLPNDGQ
  CHLENNMYTMSHYYDYPSIAHLVQKLSENNIQTIFAVTEEFQPVYKELKNLIPKSAVGTL
  SANSSNVIQLIIDAYNSLSSEVILENGKLSEGVTISYKSYCKNGVNGTGENGRKCSNISI
  GDEVQFEISITSNKCPKKDSDSFKIRPLGFTEEVEVILQYICECECQSEGIPESPKCHEG
  NGTFECGACRCNEGRVGRHCECSTDEVNSEDMDAYCRKENSSEICSNNGECVCGQCVCRK
  RDNTNEIYSGKFCECDNFNCDRSNGLICGGNGVCKCRVCECNPNYTGSACDCSLDTSTCE
  ASNGQICNGRGICECGVCKCTDPKFQGQTCEMCQTCLGVCAEHKECVQCRAFNKGEKKDT
  CTQECSYFNITKVESRDKLPQPVQPDPVSHCKEKDVDDCWFYFTYSVNGNNEVMVHVVEN
  PECPTGPDIIPIVAGVVAGIVLIGLALLLIWKLLMIIHDRREFAKFEKEKMNAKWDTGEN
  PIYKSAVTTVVNPKYEGK
• Function: Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion. Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. Isoform 2 interferes with isoform 1 resulting in a dominant negative effect on cell adhesion and migration (in vitro). When associated with alpha-7/beta-1 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGA4:ITGB1 and ITGA5:ITGB1 bind 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. ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1. ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling. Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen.
• KEGG Pathway:
  Rap1 signaling pathway (hsa04015)
  Phagosome (hsa04145)
  PI3K-Akt signaling pathway (hsa04151)
  Axon guidance (hsa04360)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (CAMs) (hsa04514)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Pertussis (hsa05133)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  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:
  Fibronectin matrix formation (R-HSA-1566977)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Basigin interactions (R-HSA-210991)
  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)
  Other semaphorin interactions (R-HSA-416700)
  Localization of the PINCH-ILK-PARVIN complex to focal adhesions (R-HSA-446343)
  CHL1 interactions (R-HSA-447041)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Platelet Adhesion to exposed collagen (R-HSA-75892)
  Elastic fibre formation (R-HSA-1566948)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
131I-radretumab	DMT17XU	Non-small-cell lung cancer	2C25.Y	Phase 1/2	[1]
JSM 6427	DM4QIOH	Macular degeneration	9B78.3	Phase 1	[2]
OS2966	DMS8NM5	Glioblastoma of brain	2A00.00	Phase 1	[3]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
C(-GRGDfL-)	DMTMJAI	Discovery agent	N.A.	Investigative	[4]
MK-0668	DMVBFJP	Discovery agent	N.A.	Investigative	[5]
SB-265123	DM8UKH7	Discovery agent	N.A.	Investigative	[6]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Lung cancer	2C82	Lung tissue	6.67E-01	-0.03	-0.12
Asthma	CA23	Nasal and bronchial airway	2.98E-03	-0.07	-0.04

References

• [1] Radretumab radioimmunotherapy in patients with brain metastasis: a 124I-L19SIP dosimetric PET study. Cancer Immunol Res. 2013 Aug;1(2):134-43.
• [2] An alpha5beta1 integrin inhibitor attenuates glioma growth. Mol Cell Neurosci. 2008 Dec;39(4):579-85.
• [3] Convection-Enhanced Delivery of a First-in-Class Anti-beta1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging. Pharmaceutics. 2020 Dec 30;13(1):40.
• [4] Multiple N-methylation by a designed approach enhances receptor selectivity. J Med Chem. 2007 Nov 29;50(24):5878-81.
• [5] Discovery of N-{N-[(3-cyanobenzene) sulfonyl]-4(R)-(3,3-difluoropiperidin-1-yl)-(l)-prolyl}-4-[(3',5'-dichloro-isonicotinoyl) amino]-(l)-phenylalan... Bioorg Med Chem Lett. 2009 Oct 1;19(19):5803-6.
• [6] Orally bioavailable nonpeptide vitronectin receptor antagonists with efficacy in an osteoporosis model. Bioorg Med Chem Lett. 1999 Jul 5;9(13):1807-12.