Details of Drug Off-Target (DOT)

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

• DOT Name: Zinc finger protein ZIC 3
• Synonyms: Zinc finger protein 203; Zinc finger protein of the cerebellum 3
• Gene Name: ZIC3
• Related Disease:
  Heterotaxy, visceral, 1, X-linked
  VACTERL association, X-linked, with or without hydrocephalus
• UniProt ID: ZIC3_HUMAN
• PDB ID: 2EJ4; 2RPC
• Pfam ID: PF00096 ; PF18366
• Sequence:
  MTMLLDGGPQFPGLGVGSFGAPRHHEMPNREPAGMGLNPFGDSTHAAAAAAAAAAFKLSP
  AAAHDLSSGQSSAFTPQGSGYANALGHHHHHHHHHHHTSQVPSYGGAASAAFNSTREFLF
  RQRSSGLSEAASGGGQHGLFAGSASSLHAPAGIPEPPSYLLFPGLHEQGAGHPSPTGHVD
  NNQVHLGLRGELFGRADPYRPVASPRTDPYAAGAQFPNYSPMNMNMGVNVAAHHGPGAFF
  RYMRQPIKQELSCKWIDEAQLSRPKKSCDRTFSTMHELVTHVTMEHVGGPEQNNHVCYWE
  ECPREGKSFKAKYKLVNHIRVHTGEKPFPCPFPGCGKIFARSENLKIHKRTHTGEKPFKC
  EFEGCDRRFANSSDRKKHMHVHTSDKPYICKVCDKSYTHPSSLRKHMKVHESQGSDSSPA
  ASSGYESSTPPAIASANSKDTTKTPSAVQTSTSHNPGLPPNFNEWYV
• Function: Acts as a transcriptional activator. Required in the earliest stages in both axial midline development and left-right (LR) asymmetry specification. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Transcriptional regulation of pluripotent stem cells (R-HSA-452723)
  POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation (R-HSA-2892247)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Heterotaxy, visceral, 1, X-linked	DIS01H96	Definitive	X-linked recessive	[1]
VACTERL association, X-linked, with or without hydrocephalus	DISGDBX3	Definitive	X-linked recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Zinc finger protein ZIC 3.	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Zinc finger protein ZIC 3.	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger protein ZIC 3.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein ZIC 3.	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Zinc finger protein ZIC 3.	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Zinc finger protein ZIC 3.	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Zinc finger protein ZIC 3.	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Zinc finger protein ZIC 3.	[6]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Zinc finger protein ZIC 3.	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Zinc finger protein ZIC 3.	[9]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 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.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] 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.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] 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.
• [8] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.