Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2GX84M)

• DOT Name: GDNF-inducible zinc finger protein 1 (GZF1)
• Synonyms: Zinc finger and BTB domain-containing protein 23; Zinc finger protein 336
• Gene Name: GZF1
• Related Disease:
  Joint laxity, short stature, and myopia
  Larsen syndrome
• UniProt ID: GZF1_HUMAN
• Pfam ID: PF00651 ; PF00096 ; PF13912
• Sequence:
  MESGAVLLESKSSPFNLLHEMHELRLLGHLCDVTVSVEYQGVRKDFMAHKAVLAATSKFF
  KEVFLNEKSVDGTRTNVYLNEVQVADFASFLEFVYTAKVQVEEDRVQRMLEVAEKLKCLD
  LSETCFQLKKQMLESVLLELQNFSESQEVEVSSGSQVSAAPAPRASVATDGPHPSGLTDS
  LDYPGERASNGMSSDLPPKKSKDKLDKKKEVVKPPYPKIRRASGRLAGRKVFVEIPKKKY
  TRRLREQQKTAEGDVGDYRCPQDQSPDRVGTEMEQVSKNEGCQAGAELEELSKKAGPEEE
  EEEEEEDEEGEKKKSNFKCSICEKAFLYEKSFLKHSKHRHGVATEVVYRCDTCGQTFANR
  CNLKSHQRHVHSSERHFPCELCGKKFKRKKDVKRHVLQVHEGGGERHRCGQCGKGLSSKT
  ALRLHERTHTGDRPYGCTECGARFSQPSALKTHMRIHTGEKPFVCDECGARFTQNHMLIY
  HKRCHTGERPFMCETCGKSFASKEYLKHHNRIHTGSKPFKCEVCFRTFAQRNSLYQHIKV
  HTGERPYCCDQCGKQFTQLNALQRHRRIHTGERPFMCNACGRTFTDKSTLRRHTSIHDKN
  TPWKSFLVIVDGSPKNDDGHKTEQPDEEYVSSKLSDKLLSFAENGHFHNLAAVQDTVPTM
  QENSSADTACKADDSVVSQDTLLATTISELSELTPQTDSMPTQLHSLSNME
• Function: Transcriptional repressor that binds the GZF1 responsive element (GRE) (consensus: 5'-TGCGCN[TG][CA]TATA-3'). May be regulating VSX2/HOX10 expression.
• Tissue Specificity: Expressed in adult brain, heart, skeletal muscle, kidney and liver. Also detected in fetal brain and kidney, and at lower levels in fetal lung and liver.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joint laxity, short stature, and myopia	DISYDDUS	Strong	Autosomal recessive	[1]
Larsen syndrome	DISDRPMA	Strong	Autosomal recessive	[2]

12 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 GDNF-inducible zinc finger protein 1 (GZF1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of GDNF-inducible zinc finger protein 1 (GZF1).	[15]

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 affects the phosphorylation of GDNF-inducible zinc finger protein 1 (GZF1).	[14]

References

• [1] Novel GZF1 pathogenic variants identified in two Chinese patients with Larsen syndrome. Clin Genet. 2021 Feb;99(2):281-285. doi: 10.1111/cge.13856. Epub 2020 Oct 10.
• [2] GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome. Am J Hum Genet. 2017 May 4;100(5):831-836. doi: 10.1016/j.ajhg.2017.04.008.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.
• [15] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.