Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4BT06)

• DTT Name: Integrin alpha-4 (ITGA4)
• Synonyms: Very late antigen 4; VLA4 subunit alpha; VLA-4 subunit alpha; VLA-4; Integrin alphaIV; Integrin alpha4; Integrin alpha-IV; CD49d; CD49 antigenlike family member D; CD49 antigen-like family member D
• Gene Name: ITGA4
• DTT Type: Successful target; [1]
• BioChemical Class: Integrin
• UniProt ID: ITA4_HUMAN
• TTD ID: T97587
• Sequence:
  MAWEARREPGPRRAAVRETVMLLLCLGVPTGRPYNVDTESALLYQGPHNTLFGYSVVLHS
  HGANRWLLVGAPTANWLANASVINPGAIYRCRIGKNPGQTCEQLQLGSPNGEPCGKTCLE
  ERDNQWLGVTLSRQPGENGSIVTCGHRWKNIFYIKNENKLPTGGCYGVPPDLRTELSKRI
  APCYQDYVKKFGENFASCQAGISSFYTKDLIVMGAPGSSYWTGSLFVYNITTNKYKAFLD
  KQNQVKFGSYLGYSVGAGHFRSQHTTEVVGGAPQHEQIGKAYIFSIDEKELNILHEMKGK
  KLGSYFGASVCAVDLNADGFSDLLVGAPMQSTIREEGRVFVYINSGSGAVMNAMETNLVG
  SDKYAARFGESIVNLGDIDNDGFEDVAIGAPQEDDLQGAIYIYNGRADGISSTFSQRIEG
  LQISKSLSMFGQSISGQIDADNNGYVDVAVGAFRSDSAVLLRTRPVVIVDASLSHPESVN
  RTKFDCVENGWPSVCIDLTLCFSYKGKEVPGYIVLFYNMSLDVNRKAESPPRFYFSSNGT
  SDVITGSIQVSSREANCRTHQAFMRKDVRDILTPIQIEAAYHLGPHVISKRSTEEFPPLQ
  PILQQKKEKDIMKKTINFARFCAHENCSADLQVSAKIGFLKPHENKTYLAVGSMKTLMLN
  VSLFNAGDDAYETTLHVKLPVGLYFIKILELEEKQINCEVTDNSGVVQLDCSIGYIYVDH
  LSRIDISFLLDVSSLSRAEEDLSITVHATCENEEEMDNLKHSRVTVAIPLKYEVKLTVHG
  FVNPTSFVYGSNDENEPETCMVEKMNLTFHVINTGNSMAPNVSVEIMVPNSFSPQTDKLF
  NILDVQTTTGECHFENYQRVCALEQQKSAMQTLKGIVRFLSKTDKRLLYCIKADPHCLNF
  LCNFGKMESGKEASVHIQLEGRPSILEMDETSALKFEIRATGFPEPNPRVIELNKDENVA
  HVLLEGLHHQRPKRYFTIVIISSSLLLGLIVLLLISYVMWKAGFFKRQYKSILQEENRRD
  SWSYINSKSNDD
• 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. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling. ITGA4:ITGB1 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.
• 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:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Integrin cell surface interactions (R-HSA-216083)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Antegren	DMNC64R	Multiple sclerosis	8A40	Approved	[2]
Natalizumab	DMAK85L	Crohn disease	DD70	Approved	[3]
Vedolizmab	DMV3YMX	Crohn disease	DD70	Approved	[1]

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PB006	DMVHGLA	Crohn disease	DD70	Phase 3	[4]
AMG-181	DMODJTX	Crohn disease	DD70	Phase 2	[5]
BIO-1211	DMKICA3	Asthma	CA23	Phase 2	[6]
GSK683699	DMTW79H	Inflammatory bowel disease	DD72	Phase 2	[7]
Senktide	DMOH8LD	Epilepsy	8A60-8A68	Phase 2	[8]
ELND-002	DMM9S51	Autoimmune diabetes	5A10	Phase 1	[9]
ELND-004	DMLQYVD	Autoimmune diabetes	5A10	Phase 1	[9]
PTG-100	DMQNRGE	Ulcerative colitis	DD71	Phase 1	[5]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASP-2002	DM3XCM1	Ulcerative colitis	DD71	Investigative	[10]
CT301	DMUVQFW	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
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] Clinical pipeline report, company report or official report of Takeda (2009).
• [2] Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents. Curr Opin Chem Biol. 1998 Aug;2(4):453-7.
• [3] Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring. Front Immunol. 2020 Sep 24;11:549842.
• [4] Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis: The Antelope Phase 3 Randomized Clinical Trial. JAMA Neurol. 2023 Mar 1;80(3):298-307.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] A small-molecule, tight-binding inhibitor of the integrin alpha(4)beta(1) blocks antigen-induced airway responses and inflammation in experimental asthma in sheep. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):603-11.
• [7] Emerging drugs to treat Crohn's disease. Expert Opin Emerg Drugs. 2007 Mar;12(1):49-59.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Paxillin binding to the alpha 4 integrin subunit stimulates LFA-1 (integrin alpha L beta 2)-dependent T cell migration by augmenting the activation of focal adhesion kinase/proline-rich tyrosine kinase-2. J Immunol. 2003 Jun 15;170(12):5912-8.
• [10] Asphelia to Present at C21 BioVentures Conference in Napa, CA. 10th Annual C21 BioVentures. May 15, 2008.
• [11] Prolonged reversal of chronic experimental allergic encephalomyelitis using a small molecule inhibitor of alpha4 integrin. J Neuroimmunol. 2002 Oct;131(1-2):147-59.