Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVWYJS9)

• DOT Name: Target of EGR1 protein 1 (TOE1)
• Gene Name: TOE1
• Related Disease:
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia type 7
  Hereditary neoplastic syndrome
• UniProt ID: TOE1_HUMAN
• PDB ID: 2FC6
• Pfam ID: PF04857 ; PF00642
• Sequence:
  MAADSDDGAVSAPAASDGGVSKSTTSGEELVVQVPVVDVQSNNFKEMWPSLLLAIKTANF
  VAVDTELSGLGDRKSLLNQCIEERYKAVCHAARTRSILSLGLACFKRQPDKGEHSYLAQV
  FNLTLLCMEEYVIEPKSVQFLIQHGFNFNQQYAQGIPYHKGNDKGDESQSQSVRTLFLEL
  IRARRPLVLHNGLIDLVFLYQNFYAHLPESLGTFTADLCEMFPAGIYDTKYAAEFHARFV
  ASYLEYAFRKCERENGKQRAAGSPHLTLEFCNYPSSMRDHIDYRCCLPPATHRPHPTSIC
  DNFSAYGWCPLGPQCPQSHDIDLIIDTDEAAAEDKRRRRRRREKRKRALLNLPGTQTSGE
  AKDGPPKKQVCGDSIKPEETEQEVAADETRNLPHSKQGNKNDLEMGIKAARPEIADRATS
  EVPGSQASPNPVPGDGLHRAGFDAFMTGYVMAYVEVSQGPQPCSSGPWLPECHNKVYLSG
  KAVPLTVAKSQFSRSSKAHNQKMKLTWGSS
• Function: Inhibits cell growth rate and cell cycle. Induces CDKN1A expression as well as TGF-beta expression. Mediates the inhibitory growth effect of EGR1. Involved in the maturation of snRNAs and snRNA 3'-tail processing.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pontocerebellar hypoplasia	DISRICMU	Strong	Genetic Variation	[1]
Pontocerebellar hypoplasia type 7	DISXFITF	Strong	Autosomal recessive	[1]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Target of EGR1 protein 1 (TOE1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Target of EGR1 protein 1 (TOE1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Target of EGR1 protein 1 (TOE1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Target of EGR1 protein 1 (TOE1).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Target of EGR1 protein 1 (TOE1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Target of EGR1 protein 1 (TOE1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Target of EGR1 protein 1 (TOE1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Target of EGR1 protein 1 (TOE1).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Target of EGR1 protein 1 (TOE1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Target of EGR1 protein 1 (TOE1).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Target of EGR1 protein 1 (TOE1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Target of EGR1 protein 1 (TOE1).	[13]

References

• [1] Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet. 2017 Mar;49(3):457-464. doi: 10.1038/ng.3762. Epub 2017 Jan 16.
• [2] Base excision repair and the role of MUTYH.Hered Cancer Clin Pract. 2007 Dec 15;5(4):199-209. doi: 10.1186/1897-4287-5-4-199.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.