Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6S84X)

• DTT Name: Integrin alpha-4/beta-1 (ITGA4/B1)
• Synonyms: alpha(4)beta(1) integrin; Alpha 4 beta 1 integrin
• Gene Name: ITGA4-ITGB1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Integrin
• UniProt ID: ITA4_HUMAN-ITB1_HUMAN
• TTD ID: T86130
• Sequence:
  MNLQPIFWIGLISSVCCVFAQTDENRCLKANAKSCGECIQAGPNCGWCTNSTFLQEGMPT
  SARCDDLEALKKKGCPPDDIENPRGSKDIKKNKNVTNRSKGTAEKLKPEDITQIQPQQLV
  LRLRSGEPQTFTLKFKRAEDYPIDLYYLMDLSYSMKDDLENVKSLGTDLMNEMRRITSDF
  RIGFGSFVEKTVMPYISTTPAKLRNPCTSEQNCTSPFSYKNVLSLTNKGEVFNELVGKQR
  ISGNLDSPEGGFDAIMQVAVCGSLIGWRNVTRLLVFSTDAGFHFAGDGKLGGIVLPNDGQ
  CHLENNMYTMSHYYDYPSIAHLVQKLSENNIQTIFAVTEEFQPVYKELKNLIPKSAVGTL
  SANSSNVIQLIIDAYNSLSSEVILENGKLSEGVTISYKSYCKNGVNGTGENGRKCSNISI
  GDEVQFEISITSNKCPKKDSDSFKIRPLGFTEEVEVILQYICECECQSEGIPESPKCHEG
  NGTFECGACRCNEGRVGRHCECSTDEVNSEDMDAYCRKENSSEICSNNGECVCGQCVCRK
  RDNTNEIYSGKFCECDNFNCDRSNGLICGGNGVCKCRVCECNPNYTGSACDCSLDTSTCE
  ASNGQICNGRGICECGVCKCTDPKFQGQTCEMCQTCLGVCAEHKECVQCRAFNKGEKKDT
  CTQECSYFNITKVESRDKLPQPVQPDPVSHCKEKDVDDCWFYFTYSVNGNNEVMVHVVEN
  PECPTGPDIIPIVAGVVAGIVLIGLALLLIWKLLMIIHDRREFAKFEKEKMNAKWDTGEN
  PIYKSAVTTVVNPKYEGKMAWEARREPGPRRAAVRETVMLLLCLGVPTGRPYNVDTESAL
  LYQGPHNTLFGYSVVLHSHGANRWLLVGAPTANWLANASVINPGAIYRCRIGKNPGQTCE
  QLQLGSPNGEPCGKTCLEERDNQWLGVTLSRQPGENGSIVTCGHRWKNIFYIKNENKLPT
  GGCYGVPPDLRTELSKRIAPCYQDYVKKFGENFASCQAGISSFYTKDLIVMGAPGSSYWT
  GSLFVYNITTNKYKAFLDKQNQVKFGSYLGYSVGAGHFRSQHTTEVVGGAPQHEQIGKAY
  IFSIDEKELNILHEMKGKKLGSYFGASVCAVDLNADGFSDLLVGAPMQSTIREEGRVFVY
  INSGSGAVMNAMETNLVGSDKYAARFGESIVNLGDIDNDGFEDVAIGAPQEDDLQGAIYI
  YNGRADGISSTFSQRIEGLQISKSLSMFGQSISGQIDADNNGYVDVAVGAFRSDSAVLLR
  TRPVVIVDASLSHPESVNRTKFDCVENGWPSVCIDLTLCFSYKGKEVPGYIVLFYNMSLD
  VNRKAESPPRFYFSSNGTSDVITGSIQVSSREANCRTHQAFMRKDVRDILTPIQIEAAYH
  LGPHVISKRSTEEFPPLQPILQQKKEKDIMKKTINFARFCAHENCSADLQVSAKIGFLKP
  HENKTYLAVGSMKTLMLNVSLFNAGDDAYETTLHVKLPVGLYFIKILELEEKQINCEVTD
  NSGVVQLDCSIGYIYVDHLSRIDISFLLDVSSLSRAEEDLSITVHATCENEEEMDNLKHS
  RVTVAIPLKYEVKLTVHGFVNPTSFVYGSNDENEPETCMVEKMNLTFHVINTGNSMAPNV
  SVEIMVPNSFSPQTDKLFNILDVQTTTGECHFENYQRVCALEQQKSAMQTLKGIVRFLSK
  TDKRLLYCIKADPHCLNFLCNFGKMESGKEASVHIQLEGRPSILEMDETSALKFEIRATG
  FPEPNPRVIELNKDENVAHVLLEGLHHQRPKRYFTIVIISSSLLLGLIVLLLISYVMWKA
  GFFKRQYKSILQEENRRDSWSYINSKSNDD
• Function: Integrins alpha-4/beta-1 (VLA-4) and alpha-4/beta-7 are receptors for fibronectin. They recognize one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. They are also receptors for VCAM1. Integrin alpha- 4/beta-1 recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha- 4/beta-7 is also a receptor for MADCAM1. It recognizes the sequence L-D-T in MADCAM1. On activated endothelial cells integrin VLA-4 triggers homotypic aggregation for most VLA-4-positive leukocyte cell lines. It may also participate in cytolytic T-cell interactions with target cells.
• KEGG Pathway:
  PI3K-Akt signaling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (CAMs) (hsa04514)
  Hematopoietic cell lineage (hsa04640)
  Leukocyte transendothelial migration (hsa04670)
  Intestinal immune network for IgA production (hsa04672)
  Regulation of actin cytoskeleton (hsa04810)
  Leishmaniasis (hsa05140)
  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)
  Elastic fibre formation (R-HSA-1566948)

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
AJM-300	DM5K6J4	Crohn disease	DD70	Phase 3	[1]
CDP323	DMXYLTI	Multiple sclerosis	8A40	Phase 2	[2]
Firategrast	DMW2QYT	Multiple sclerosis	8A40	Phase 2	[3]
R411	DMP7J0S	Asthma	CA23	Phase 2	[4]
TRK-170	DM13G5R	Inflammatory bowel disease	DD72	Phase 2	[5]
BIIB107	DMIA57S	Multiple sclerosis	8A40	Phase 1	[6]
HMR-1031	DM695QT	Arthritis	FA20	Phase 1	[7]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TR-14035	DMWD39E	Multiple sclerosis	8A40	Discontinued in Phase 1	[8]
CY-9652	DMPBCLA	Inflammation	1A00-CA43.1	Terminated	[9]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TCS2314	DMBVYQR	Discovery agent	N.A.	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	1.30E-02	-0.26	-0.21
Rheumatoid arthritis	FA20	Synovial tissue	9.70E-14	1.52	7.72

References

• [1] Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J Crohns Colitis. 2013 Dec;7(11):e533-42.
• [2] Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study.PLoS One.2013;8(3):e58438.
• [3] Firategrast for relapsing remitting multiple sclerosis: a phase 2, randomised, double-blind, placebo-controlled trial.Lancet Neurol.2012 Feb;11(2):131-9.
• [4] Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov. 2010 Oct;9(10):804-20.
• [5] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [6] ClinicalTrials.gov (NCT04593121) A Phase 1, Randomized, Blinded, Placebo-Controlled, Single- and Multiple-Ascending-Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB107 in Healthy Adult Participants. U.S.National Institutes of Health.
• [7] Pharmacoscintigraphic comparison of HMR 1031, a VLA-4 antagonist, in healthy volunteers following delivery via a nebulizer and a dry powder inhaler. Am J Ther. 2004 Mar-Apr;11(2):103-13.
• [8] Pharmacokinetics and metabolism of TR-14035, a novel antagonist of a4ss1/a4ss7 integrin mediated cell adhesion, in rat and dog. Xenobiotica. 2005 Apr;35(4):373-89.
• [9] US patent application no. 2010,0278,784, Methods and compositions for treating skin conditions.
• [10] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2580).