Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOUVAG5)

• DOT Name: Zinc finger and BTB domain-containing protein 18
• Synonyms: 58 kDa repressor protein; Transcriptional repressor RP58; Translin-associated zinc finger protein 1; TAZ-1; Zinc finger protein 238; Zinc finger protein C2H2-171
• Gene Name: ZBTB18
• Related Disease:
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 22
• UniProt ID: ZBT18_HUMAN
• Pfam ID: PF00651 ; PF00096 ; PF13894
• Sequence:
  MEFPDHSRHLLQCLSEQRHQGFLCDCTVLVGDAQFRAHRAVLASCSMYFHLFYKDQLDKR
  DIVHLNSDIVTAPAFALLLEFMYEGKLQFKDLPIEDVLAAASYLHMYDIVKVCKKKLKEK
  ATTEADSTKKEEDASSCSDKVESLSDGSSHIAGDLPSDEDEGEDEKLNILPSKRDLAAEP
  GNMWMRLPSDSAGIPQAGGEAEPHATAAGKTVASPCSSTESLSQRSVTSVRDSADVDCVL
  DLSVKSSLSGVENLNSSYFSSQDVLRSNLVQVKVEKEASCDESDVGTNDYDMEHSTVKES
  VSTNNRVQYEPAHLAPLREDSVLRELDREDKASDDEMMTPESERVQVEGGMESSLLPYVS
  NILSPAGQIFMCPLCNKVFPSPHILQIHLSTHFREQDGIRSKPAADVNVPTCSLCGKTFS
  CMYTLKRHERTHSGEKPYTCTQCGKSFQYSHNLSRHAVVHTREKPHACKWCERRFTQSGD
  LYRHIRKFHCELVNSLSVKSEALSLPTVRDWTLEDSSQELWK
• Function: Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development. Plays a key role in myogenesis by directly repressing the expression of ID2 and ID3, 2 inhibitors of skeletal myogenesis. Also involved in controlling cell division of progenitor cells and regulating the survival of postmitotic cortical neurons. Specifically binds the consensus DNA sequence 5'-[AC]ACATCTG[GT][AC]-3' which contains the E box core, and acts by recruiting chromatin remodeling multiprotein complexes. May also play a role in the organization of chromosomes in the nucleus.
• Tissue Specificity: Lymphoid tissues, testis, heart, brain, skeletal muscle, and pancreas and, at much lower level, other tissues.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Intellectual disability, autosomal dominant 22	DISE721U	Definitive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Zinc finger and BTB domain-containing protein 18 increases the Metabolic disorder ADR of Chlorothiazide.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Zinc finger and BTB domain-containing protein 18.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Zinc finger and BTB domain-containing protein 18.	[4]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Zinc finger and BTB domain-containing protein 18.	[5]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Zinc finger and BTB domain-containing protein 18.	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Zinc finger and BTB domain-containing protein 18.	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Zinc finger and BTB domain-containing protein 18.	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Zinc finger and BTB domain-containing protein 18.	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Zinc finger and BTB domain-containing protein 18.	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Zinc finger and BTB domain-containing protein 18.	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Zinc finger and BTB domain-containing protein 18.	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Zinc finger and BTB domain-containing protein 18.	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Zinc finger and BTB domain-containing protein 18.	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A de novo non-sense mutation in ZBTB18 in a patient with features of the 1q43q44 microdeletion syndrome. Eur J Hum Genet. 2014 Jun;22(6):844-6. doi: 10.1038/ejhg.2013.249. Epub 2013 Nov 6.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [6] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] 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.
• [10] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [14] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [15] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.