Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEQK65P)

• DOT Name: Angiopoietin-2 (ANGPT2)
• Synonyms: ANG-2
• Gene Name: ANGPT2
• Related Disease: Lymphatic malformation 10
• UniProt ID: ANGP2_HUMAN
• PDB ID: 1Z3S; 1Z3U; 2GY7; 4JZC; 4ZFG
• Pfam ID: PF00147
• Sequence:
  MWQIVFFTLSCDLVLAAAYNNFRKSMDSIGKKQYQVQHGSCSYTFLLPEMDNCRSSSSPY
  VSNAVQRDAPLEYDDSVQRLQVLENIMENNTQWLMKLENYIQDNMKKEMVEIQQNAVQNQ
  TAVMIEIGTNLLNQTAEQTRKLTDVEAQVLNQTTRLELQLLEHSLSTNKLEKQILDQTSE
  INKLQDKNSFLEKKVLAMEDKHIIQLQSIKEEKDQLQVLVSKQNSIIEELEKKIVTATVN
  NSVLQKQQHDLMETVNNLLTMMSTSNSAKDPTVAKEEQISFRDCAEVFKSGHTTNGIYTL
  TFPNSTEEIKAYCDMEAGGGGWTIIQRREDGSVDFQRTWKEYKVGFGNPSGEYWLGNEFV
  SQLTNQQRYVLKIHLKDWEGNEAYSLYEHFYLSSEELNYRIHLKGLTGTAGKISSISQPG
  NDFSTKDGDNDKCICKCSQMLTGGWWFDACGPSNLNGMYYPQRQNTNKFNGIKWYYWKGS
  GYSLKATTMMIRPADF
• Function: Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1. In the absence of angiogenic inducers, such as VEGF, ANGPT2-mediated loosening of cell-matrix contacts may induce endothelial cell apoptosis with consequent vascular regression. In concert with VEGF, it may facilitate endothelial cell migration and proliferation, thus serving as a permissive angiogenic signal. Involved in the regulation of lymphangiogenesis.
• 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)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway: Tie2 Signaling (R-HSA-210993)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lymphatic malformation 10	DIS3BKJI	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Angiopoietin-2 (ANGPT2).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Angiopoietin-2 (ANGPT2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Angiopoietin-2 (ANGPT2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Angiopoietin-2 (ANGPT2).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Angiopoietin-2 (ANGPT2).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Angiopoietin-2 (ANGPT2).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Angiopoietin-2 (ANGPT2).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Angiopoietin-2 (ANGPT2).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Angiopoietin-2 (ANGPT2).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Angiopoietin-2 (ANGPT2).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Angiopoietin-2 (ANGPT2).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Angiopoietin-2 (ANGPT2).	[8]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Angiopoietin-2 (ANGPT2).	[12]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Angiopoietin-2 (ANGPT2).	[13]
Thalidomide	DM70BU5	Approved	Thalidomide affects the expression of Angiopoietin-2 (ANGPT2).	[14]
Propranolol	DM79NTF	Approved	Propranolol decreases the expression of Angiopoietin-2 (ANGPT2).	[15]
Iloprost	DMVPZBE	Approved	Iloprost increases the expression of Angiopoietin-2 (ANGPT2).	[16]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Angiopoietin-2 (ANGPT2).	[17]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the expression of Angiopoietin-2 (ANGPT2).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Angiopoietin-2 (ANGPT2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Angiopoietin-2 (ANGPT2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Angiopoietin-2 (ANGPT2).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Angiopoietin-2 (ANGPT2).	[21]
NORCANTHARIDIN	DM9B6Y1	Investigative	NORCANTHARIDIN decreases the expression of Angiopoietin-2 (ANGPT2).	[22]

References

• [1] Characterization of ANGPT2 mutations associated with primary lymphedema. Sci Transl Med. 2020 Sep 9;12(560):eaax8013. doi: 10.1126/scitranslmed.aax8013.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts. Biomed Res Int. 2015;2015:257090. doi: 10.1155/2015/257090. Epub 2015 Aug 3.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Effects of methotrexate on vascular endothelial growth factor, angiopoietin 1, and angiopoietin 2 in nasal polyps. Am J Rhinol Allergy. 2011 Jul-Aug;25(4):e129-32. doi: 10.2500/ajra.2011.25.3618.
• [10] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [11] Combination therapy of interferon-alpha and 5-fluorouracil inhibits tumor angiogenesis in human hepatocellular carcinoma cells by regulating vascular endothelial growth factor and angiopoietins. Oncol Rep. 2007 Oct;18(4):801-9.
• [12] Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. Carcinogenesis. 2011 May;32(5):686-94. doi: 10.1093/carcin/bgr025. Epub 2011 Feb 10.
• [13] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [14] Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. J Clin Oncol. 2005 Aug 10;23(23):5334-46. doi: 10.1200/JCO.2005.03.723. Epub 2005 Jun 6.
• [15] Propranolol inhibits proliferation and induces apoptosis of hemangioma-derived endothelial cells via Akt pathway by down-regulating Ang-2 expression. Chem Biol Interact. 2020 Jan 25;316:108925. doi: 10.1016/j.cbi.2019.108925. Epub 2019 Dec 12.
• [16] Prostacyclin receptor up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1/2 pathway. Endocrinology. 2006 Apr;147(4):1697-705. doi: 10.1210/en.2005-1073. Epub 2005 Dec 22.
• [17] Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res. 2009 May;77(3):314-26.
• [18] Atorvastatin affects several angiogenic mediators in human endothelial cells. Endothelium. 2005 Sep-Dec;12(5-6):233-41.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] [Effects of norcantharidin on angiogenesis of human gallbladder carcinoma and its anti-angiogenic mechanisms]. Zhonghua Yi Xue Za Zhi. 2006 Mar 14;86(10):693-9.