Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRE3O8U)

• DOT Name: Endothelial PAS domain-containing protein 1 (EPAS1)
• Synonyms: EPAS-1; Basic-helix-loop-helix-PAS protein MOP2; Class E basic helix-loop-helix protein 73; bHLHe73; HIF-1-alpha-like factor; HLF; Hypoxia-inducible factor 2-alpha; HIF-2-alpha; HIF2-alpha; Member of PAS protein 2; PAS domain-containing protein 2
• Gene Name: EPAS1
• Related Disease:
  Erythrocytosis, familial, 4
  Obsolete autosomal dominant secondary polycythemia
• UniProt ID: EPAS1_HUMAN
• PDB ID: 1P97; 2A24; 3F1N; 3F1O; 3F1P; 3H7W; 3H82; 4GHI; 4GS9; 4PKY; 4XT2; 5KIZ; 5TBM; 5UFP; 6BVB; 6CZW; 6D09; 6D0B; 6D0C; 6I7Q; 6I7R; 6X21; 6X28; 6X2H; 6X37; 6X3D; 7Q5V; 7Q5X; 7UJV; 8CK3; 8CK4; 8CK8
• Pfam ID: PF11413 ; PF08778 ; PF00989 ; PF14598
• Sequence:
  MTADKEKKRSSSERRKEKSRDAARCRRSKETEVFYELAHELPLPHSVSSHLDKASIMRLA
  ISFLRTHKLLSSVCSENESEAEADQQMDNLYLKALEGFIAVVTQDGDMIFLSENISKFMG
  LTQVELTGHSIFDFTHPCDHEEIRENLSLKNGSGFGKKSKDMSTERDFFMRMKCTVTNRG
  RTVNLKSATWKVLHCTGQVKVYNNCPPHNSLCGYKEPLLSCLIIMCEPIQHPSHMDIPLD
  SKTFLSRHSMDMKFTYCDDRITELIGYHPEELLGRSAYEFYHALDSENMTKSHQNLCTKG
  QVVSGQYRMLAKHGGYVWLETQGTVIYNPRNLQPQCIMCVNYVLSEIEKNDVVFSMDQTE
  SLFKPHLMAMNSIFDSSGKGAVSEKSNFLFTKLKEEPEELAQLAPTPGDAIISLDFGNQN
  FEESSAYGKAILPPSQPWATELRSHSTQSEAGSLPAFTVPQAAAPGSTTPSATSSSSSCS
  TPNSPEDYYTSLDNDLKIEVIEKLFAMDTEAKDQCSTQTDFNELDLETLAPYIPMDGEDF
  QLSPICPEERLLAENPQSTPQHCFSAMTNIFQPLAPVAPHSPFLLDKFQQQLESKKTEPE
  HRPMSSIFFDAGSKASLPPCCGQASTPLSSMGGRSNTQWPPDPPLHFGPTKWAVGDQRTE
  FLGAAPLGPPVSPPHVSTFKTRSAKGFGARGPDVLSPAMVALSNKLKLKRQLEYEEQAFQ
  DLSGGDPPGGSTSHLMWKRMKNLRGGSCPLMPDKPLSANVPNDKFTQNPMRGLGHPLRHL
  PLPQPPSAISPGENSKSRFPPQCYATQYQDYSLSSAHKVSGMASRLLGPSFESYLLPELT
  RYDCEVNVPVLGSSTLLQGGDLLRALDQAT
• Function: Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX1 seems to activate CTAD.
• Tissue Specificity: Expressed in most tissues, with highest levels in placenta, lung and heart. Selectively expressed in endothelial cells.
• KEGG Pathway:
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway:
  Cellular response to hypoxia (R-HSA-1234174)
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  Transcriptional regulation of pluripotent stem cells (R-HSA-452723)
  PTK6 Expression (R-HSA-8849473)
  Neddylation (R-HSA-8951664)
  Pexophagy (R-HSA-9664873)
  Regulation of gene expression by Hypoxia-inducible Factor (R-HSA-1234158)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythrocytosis, familial, 4	DISVL7DV	Strong	Autosomal dominant	[1]
Obsolete autosomal dominant secondary polycythemia	DISKHT4L	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[17]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[18]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[19]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[17]
Ketorolac	DMI4EL5	Approved	Ketorolac decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[22]
GSK525762	DMPAWBN	Phase 1	GSK525762 increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[26]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[27]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[31]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[32]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[33]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[34]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[35]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[36]
Galangin	DM5TQ2O	Investigative	Galangin increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[9]
I-BET151	DMYRUH2	Investigative	I-BET151 increases the expression of Endothelial PAS domain-containing protein 1 (EPAS1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tempol	DMUQH78	Phase 2	Tempol affects the localization of Endothelial PAS domain-containing protein 1 (EPAS1).	[20]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX affects the localization of Endothelial PAS domain-containing protein 1 (EPAS1).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Endothelial PAS domain-containing protein 1 (EPAS1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Endothelial PAS domain-containing protein 1 (EPAS1).	[28]

References

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