Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5QODDK)

• DOT Name: Egl nine homolog 1 (EGLN1)
• Synonyms: EC 1.14.11.29; Hypoxia-inducible factor prolyl hydroxylase 2; HIF-PH2; HIF-prolyl hydroxylase 2; HPH-2; Prolyl hydroxylase domain-containing protein 2; PHD2; SM-20
• Gene Name: EGLN1
• Related Disease:
  Erythrocytosis, familial, 3
  Obsolete autosomal dominant secondary polycythemia
  Obsolete hemoglobin, high altitude adaptation
• UniProt ID: EGLN1_HUMAN
• PDB ID: 2G19 ; 2G1M ; 2HBT ; 2HBU ; 2Y33 ; 2Y34 ; 3HQR ; 3HQU ; 3OUH ; 3OUI ; 3OUJ ; 4BQW ; 4BQX ; 4BQY ; 4JZR ; 4KBZ ; 4UWD ; 5A3U ; 5L9B ; 5L9R ; 5L9V ; 5LA9 ; 5LAS ; 5LAT ; 5LB6 ; 5LBB ; 5LBC ; 5LBE ; 5LBF ; 5OX5 ; 5OX6 ; 5V18 ; 6NMQ ; 6QGV ; 6ST3 ; 6YVT ; 6YVW ; 6YVX ; 6YVZ ; 6YW0 ; 6YW1 ; 6YW2 ; 6YW3 ; 6YW4 ; 6ZBN ; 6ZBO ; 7Q5V ; 7Q5X ; 7UJV ; 7UMP
• EC Number: 1.14.11.29
• Pfam ID: PF13640 ; PF01753
• Sequence:
  MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQDWKKHKLVCQG
  SEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADP
  AAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSPGGGLR
  PNGQTKPLPALKLALEYIVPCMNKHGICVVDDFLGKETGQQIGDEVRALHDTGKFTDGQL
  VSQKSDSSKDIRGDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRTKAMV
  ACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDAKVSGGILRIFPEGKAQFADIEPKF
  DRLLFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVELNKPSDS
  VGKDVF
• Function: Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif.
• Tissue Specificity: According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle.
• KEGG Pathway:
  HIF-1 sig.ling pathway (hsa04066)
  Pathways in cancer (hsa05200)
  Re.l cell carcinoma (hsa05211)
• Reactome Pathway: Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythrocytosis, familial, 3	DIS181T8	Strong	Autosomal dominant	[1]
Obsolete autosomal dominant secondary polycythemia	DISKHT4L	Supportive	Autosomal dominant	[2]
Obsolete hemoglobin, high altitude adaptation	DISP9J8M	Limited	Autosomal dominant	[3]

27 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 Egl nine homolog 1 (EGLN1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Egl nine homolog 1 (EGLN1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Egl nine homolog 1 (EGLN1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Egl nine homolog 1 (EGLN1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Egl nine homolog 1 (EGLN1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Egl nine homolog 1 (EGLN1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Egl nine homolog 1 (EGLN1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Egl nine homolog 1 (EGLN1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Egl nine homolog 1 (EGLN1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Egl nine homolog 1 (EGLN1).	[13]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Egl nine homolog 1 (EGLN1).	[14]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Egl nine homolog 1 (EGLN1).	[15]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Egl nine homolog 1 (EGLN1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Egl nine homolog 1 (EGLN1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Egl nine homolog 1 (EGLN1).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Egl nine homolog 1 (EGLN1).	[11]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of Egl nine homolog 1 (EGLN1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Egl nine homolog 1 (EGLN1).	[19]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Egl nine homolog 1 (EGLN1).	[21]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Egl nine homolog 1 (EGLN1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Egl nine homolog 1 (EGLN1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Egl nine homolog 1 (EGLN1).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Egl nine homolog 1 (EGLN1).	[25]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Egl nine homolog 1 (EGLN1).	[26]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Egl nine homolog 1 (EGLN1).	[27]
Myricetin	DMTV4L0	Investigative	Myricetin decreases the expression of Egl nine homolog 1 (EGLN1).	[11]
Piceatannol	DMYOP45	Investigative	Piceatannol decreases the expression of Egl nine homolog 1 (EGLN1).	[11]

2 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 Egl nine homolog 1 (EGLN1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Egl nine homolog 1 (EGLN1).	[20]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9. doi: 10.1073/pnas.0508423103. Epub 2006 Jan 9.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Involvement of SIRT1 in hypoxic down-regulation of c-Myc and beta-catenin and hypoxic preconditioning effect of polyphenols. Toxicol Appl Pharmacol. 2012 Mar 1;259(2):210-8.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] 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.
• [14] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [15] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Andrographolide down-regulates hypoxia-inducible factor-1 in human non-small cell lung cancer A549 cells. Toxicol Appl Pharmacol. 2011 Feb 1;250(3):336-45. doi: 10.1016/j.taap.2010.11.014. Epub 2010 Dec 4.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [22] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [26] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.
• [27] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.