Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVZ1NG3)

• DOT Name: Angiopoietin-1 (ANGPT1)
• Synonyms: ANG-1
• Gene Name: ANGPT1
• Related Disease:
  Glaucoma
  Primary congenital glaucoma
• UniProt ID: ANGP1_HUMAN
• PDB ID: 4EPU; 4JYO; 4K0V
• Pfam ID: PF00147
• Sequence:
  MTVFLSFAFLAAILTHIGCSNQRRSPENSGRRYNRIQHGQCAYTFILPEHDGNCRESTTD
  QYNTNALQRDAPHVEPDFSSQKLQHLEHVMENYTQWLQKLENYIVENMKSEMAQIQQNAV
  QNHTATMLEIGTSLLSQTAEQTRKLTDVETQVLNQTSRLEIQLLENSLSTYKLEKQLLQQ
  TNEILKIHEKNSLLEHKILEMEGKHKEELDTLKEEKENLQGLVTRQTYIIQELEKQLNRA
  TTNNSVLQKQQLELMDTVHNLVNLCTKEGVLLKGGKREEEKPFRDCADVYQAGFNKSGIY
  TIYINNMPEPKKVFCNMDVNGGGWTVIQHREDGSLDFQRGWKEYKMGFGNPSGEYWLGNE
  FIFAITSQRQYMLRIELMDWEGNRAYSQYDRFHIGNEKQNYRLYLKGHTGTAGKQSSLIL
  HGADFSTKDADNDNCMCKCALMLTGGWWFDACGPSNLNGMFYTAGQNHGKLNGIKWHYFK
  GPSYSLRSTTMMIRPLDF
• Function: Binds and activates TEK/TIE2 receptor by inducing its dimerization and tyrosine phosphorylation. Plays an important role in the regulation of angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Required for normal angiogenesis and heart development during embryogenesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. Mediates blood vessel maturation/stability. Implicated in endothelial developmental processes later and distinct from that of VEGF. Appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  HIF-1 sig.ling pathway (hsa04066)
  PI3K-Akt sig.ling pathway (hsa04151)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  Tie2 Signaling (R-HSA-210993)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma	DISSBT20	Moderate	Autosomal dominant	[1]
Primary congenital glaucoma	DISY7HN4	Limited	Autosomal dominant	[2]

30 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Angiopoietin-1 (ANGPT1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Angiopoietin-1 (ANGPT1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Angiopoietin-1 (ANGPT1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Angiopoietin-1 (ANGPT1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Angiopoietin-1 (ANGPT1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Angiopoietin-1 (ANGPT1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Angiopoietin-1 (ANGPT1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Angiopoietin-1 (ANGPT1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Angiopoietin-1 (ANGPT1).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Angiopoietin-1 (ANGPT1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Angiopoietin-1 (ANGPT1).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Angiopoietin-1 (ANGPT1).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Angiopoietin-1 (ANGPT1).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Angiopoietin-1 (ANGPT1).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Angiopoietin-1 (ANGPT1).	[13]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Angiopoietin-1 (ANGPT1).	[18]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Angiopoietin-1 (ANGPT1).	[19]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Angiopoietin-1 (ANGPT1).	[20]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Angiopoietin-1 (ANGPT1).	[21]
Iloprost	DMVPZBE	Approved	Iloprost increases the expression of Angiopoietin-1 (ANGPT1).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Angiopoietin-1 (ANGPT1).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Angiopoietin-1 (ANGPT1).	[15]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Angiopoietin-1 (ANGPT1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Angiopoietin-1 (ANGPT1).	[24]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Angiopoietin-1 (ANGPT1).	[25]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Angiopoietin-1 (ANGPT1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Angiopoietin-1 (ANGPT1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Angiopoietin-1 (ANGPT1).	[28]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Angiopoietin-1 (ANGPT1).	[29]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Angiopoietin-1 (ANGPT1).	[30]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cannabidiol	DM0659E	Approved	Cannabidiol increases the secretion of Angiopoietin-1 (ANGPT1).	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Angiopoietin-1 (ANGPT1).	[23]

References

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