Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5LIL3W)

• DOT Name: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN)
• Synonyms: EC 1.14.11.30; EC 1.14.11.n4; Factor inhibiting HIF-1; FIH-1; Hypoxia-inducible factor asparagine hydroxylase
• Gene Name: HIF1AN
• UniProt ID: HIF1N_HUMAN
• PDB ID: 1H2K ; 1H2L ; 1H2M ; 1H2N ; 1IZ3 ; 1MZE ; 1MZF ; 1YCI ; 2CGN ; 2CGO ; 2ILM ; 2W0X ; 2WA3 ; 2WA4 ; 2XUM ; 2Y0I ; 2YC0 ; 2YDE ; 3D8C ; 3KCX ; 3KCY ; 3OD4 ; 3P3N ; 3P3P ; 4AI8 ; 4B7E ; 4B7K ; 4BIO ; 4JAA ; 4NR1 ; 4Z1V ; 4Z2W ; 5JWK ; 5JWL ; 5JWP ; 5OP6 ; 5OP8 ; 5OPC ; 6H9J ; 6HA6 ; 6HC8 ; 6HKP ; 6HL5 ; 6HL6 ; 6RUJ ; 7A1J ; 7A1K ; 7A1L ; 7A1M ; 7A1N ; 7A1O ; 7A1P ; 7A1Q ; 7A1S
• EC Number: 1.14.11.30; 1.14.11.n4
• Pfam ID: PF13621
• Sequence:
  MAATAAEAVASGSGEPREEAGALGPAWDESQLRSYSFPTRPIPRLSQSDPRAEELIENEE
  PVVLTDTNLVYPALKWDLEYLQENIGNGDFSVYSASTHKFLYYDEKKMANFQNFKPRSNR
  EEMKFHEFVEKLQDIQQRGGEERLYLQQTLNDTVGRKIVMDFLGFNWNWINKQQGKRGWG
  QLTSNLLLIGMEGNVTPAHYDEQQNFFAQIKGYKRCILFPPDQFECLYPYPVHHPCDRQS
  QVDFDNPDYERFPNFQNVVGYETVVGPGDVLYIPMYWWHHIESLLNGGITITVNFWYKGA
  PTPKRIEYPLKAHQKVAIMRNIEKMLGEALGNPQEVGPLLNTMIKGRYN
• Function: Hydroxylates HIF-1 alpha at 'Asn-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.
• Reactome Pathway: Cellular response to hypoxia (R-HSA-1234174)
• BioCyc Pathway: MetaCyc:HS15407-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 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 Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[4]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[7]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the activity of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[10]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[11]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN).	[9]

References

• [1] In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol. 2016 Mar;90(3):677-89. doi: 10.1007/s00204-015-1483-z. Epub 2015 Feb 26.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [8] Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells. J Biol Chem. 2006 Nov 10;281(45):34056-63. doi: 10.1074/jbc.M603913200. Epub 2006 Sep 13.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Down-regulation of the expression of the FIH-1 and ARD-1 genes at the transcriptional level by nickel and cobalt in the human lung adenocarcinoma A549 cell line. Int J Environ Res Public Health. 2005 Apr;2(1):10-3. doi: 10.3390/ijerph2005010010.
• [12] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.