Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT48WR6)

• DTT Name: Integrin alpha-L (ITGAL)
• Synonyms: Lymphocyte Function-associated Antigen-1; Leukocyte function-associated molecule 1 alpha chain; Leukocyte function associated molecule 1, alpha chain; Leukocyte adhesion glycoprotein LFA-1 alpha chain; LFA-1A; LFA-1; CD11a; CD11 antigen-like family member A
• Gene Name: ITGAL
• DTT Type: Successful target; [1]
• BioChemical Class: Integrin
• UniProt ID: ITAL_HUMAN
• TTD ID: T35640
• Sequence:
  MKDSCITVMAMALLSGFFFFAPASSYNLDVRGARSFSPPRAGRHFGYRVLQVGNGVIVGA
  PGEGNSTGSLYQCQSGTGHCLPVTLRGSNYTSKYLGMTLATDPTDGSILACDPGLSRTCD
  QNTYLSGLCYLFRQNLQGPMLQGRPGFQECIKGNVDLVFLFDGSMSLQPDEFQKILDFMK
  DVMKKLSNTSYQFAAVQFSTSYKTEFDFSDYVKRKDPDALLKHVKHMLLLTNTFGAINYV
  ATEVFREELGARPDATKVLIIITDGEATDSGNIDAAKDIIRYIIGIGKHFQTKESQETLH
  KFASKPASEFVKILDTFEKLKDLFTELQKKIYVIEGTSKQDLTSFNMELSSSGISADLSR
  GHAVVGAVGAKDWAGGFLDLKADLQDDTFIGNEPLTPEVRAGYLGYTVTWLPSRQKTSLL
  ASGAPRYQHMGRVLLFQEPQGGGHWSQVQTIHGTQIGSYFGGELCGVDVDQDGETELLLI
  GAPLFYGEQRGGRVFIYQRRQLGFEEVSELQGDPGYPLGRFGEAITALTDINGDGLVDVA
  VGAPLEEQGAVYIFNGRHGGLSPQPSQRIEGTQVLSGIQWFGRSIHGVKDLEGDGLADVA
  VGAESQMIVLSSRPVVDMVTLMSFSPAEIPVHEVECSYSTSNKMKEGVNITICFQIKSLI
  PQFQGRLVANLTYTLQLDGHRTRRRGLFPGGRHELRRNIAVTTSMSCTDFSFHFPVCVQD
  LISPINVSLNFSLWEEEGTPRDQRAQGKDIPPILRPSLHSETWEIPFEKNCGEDKKCEAN
  LRVSFSPARSRALRLTAFASLSVELSLSNLEEDAYWVQLDLHFPPGLSFRKVEMLKPHSQ
  IPVSCEELPEESRLLSRALSCNVSSPIFKAGHSVALQMMFNTLVNSSWGDSVELHANVTC
  NNEDSDLLEDNSATTIIPILYPINILIQDQEDSTLYVSFTPKGPKIHQVKHMYQVRIQPS
  IHDHNIPTLEAVVGVPQPPSEGPITHQWSVQMEPPVPCHYEDLERLPDAAEPCLPGALFR
  CPVVFRQEILVQVIGTLELVGEIEASSMFSLCSSLSISFNSSKHFHLYGSNASLAQVVMK
  VDVVYEKQMLYLYVLSGIGGLLLLLLIFIVLYKVGFFKRNLKEKMEAGRGVPNGIPAEDS
  EQLASGQEAGDPGCLKPLHEKDSESGGGKD
• Function: Integrin ITGAL/ITGB2 is a receptor for F11R. Integin ITGAL/ITGB2 is a receptor for the secreted form of ubiquitin-like protein ISG15; the interaction is mediated by ITGAL. Involved in a variety of immune phenomena including leukocyte-endothelial cell interaction, cytotoxic T-cell mediated killing, and antibody dependent killing by granulocytes and monocytes. Contributes to natural killer cell cytotoxicity. Involved in leukocyte adhesion and transmigration of leukocytes including T-cells and neutrophils. Required for generation of common lymphoid progenitor cells in bone marrow, indicating a role in lymphopoiesis. Integrin ITGAL/ITGB2 in association with ICAM3, contributes to apoptotic neutrophil phagocytosis by macrophages. Integrin ITGAL/ITGB2 is a receptor for ICAM1, ICAM2, ICAM3 and ICAM4.
• KEGG Pathway:
  Rap1 signaling pathway (hsa04015)
  Cell adhesion molecules (CAMs) (hsa04514)
  Natural killer cell mediated cytotoxicity (hsa04650)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Malaria (hsa05144)
  Staphylococcus aureus infection (hsa05150)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Rheumatoid arthritis (hsa05323)
  Viral myocarditis (hsa05416)
• 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

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Efalizumab	DMCKL5V	Psoriasis vulgaris	EA90	Approved	[2]
lifitegrast	DM4WVC5	Dry eye disease	9E1Z	Approved	[1]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-587101	DMS2IC9	Psoriasis vulgaris	EA90	Discontinued in Phase 2	[3]
IC-747	DM1LVRP	Psoriasis vulgaris	EA90	Discontinued in Phase 2	[4]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cytolin	DMV8APG	Human immunodeficiency virus infection	1C62	Preclinical	[5]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
A-286982	DM98VFW	Discovery agent	N.A.	Investigative	[6]
Leukotoxin	DMYX2NJ	Autoimmune diabetes	5A10	Investigative	[7]
LFA703	DM5G307	Discovery agent	N.A.	Investigative	[8]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	1.20E-33	0.79	2.12

References

• [1] Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocul Pharmacol Ther. 2013 May;29(4):395-402.
• [2] [Successful therapy of discoid lupus erythematosus with efalizumab]. Hautarzt. 2010 Mar;61(3):246-9.
• [3] Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-(... J Med Chem. 2010 May 13;53(9):3814-30.
• [4] HECA-452+ T Cells Migrate Through Superficial Vascular Plexus but Not Through Deep Vascular Plexus Endothelium. Journal of Investigative Dermatology. 04/1997; 108(3):343-8.
• [5] Cytokine-induced phagocyte adhesion to human mesangial cells: role of CD11/CD18 integrins and ICAM-1. Am J Physiol. 1991 Dec;261(6 Pt 2):F1071-9.
• [6] Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists. Bioorg Med Chem Lett. 2010 Sep 1;20(17):5269-73.
• [7] 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: 2451).
• [8] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.