Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX468HL)

• DOT Name: Zinc finger protein 521
• Synonyms: Early hematopoietic zinc finger protein; LYST-interacting protein 3
• Gene Name: ZNF521
• UniProt ID: ZN521_HUMAN
• Pfam ID: PF00096 ; PF13912 ; PF12874
• Sequence:
  MSRRKQAKPRSLKDPNCKLEDKTEDGEALDCKKRPEDGEELEDEAVHSCDSCLQVFESLS
  DITEHKINQCQLTDGVDVEDDPTCSWPASSPSSKDQTSPSHGEGCDFGEEEGGPGLPYPC
  QFCDKSFSRLSYLKHHEQSHSDKLPFKCTYCSRLFKHKRSRDRHIKLHTGDKKYHCSECD
  AAFSRSDHLKIHLKTHTSNKPYKCAICRRGFLSSSSLHGHMQVHERNKDGSQSGSRMEDW
  KMKDTQKCSQCEEGFDFPEDLQKHIAECHPECSPNEDRAALQCVYCHELFVEETSLMNHM
  EQVHSGEKKNSCSICSESFHTVEELYSHMDSHQQPESCNHSNSPSLVTVGYTSVSSTTPD
  SNLSVDSSTMVEAAPPIPKSRGRKRAAQQTPDMTGPSSKQAKVTYSCIYCNKQLFSSLAV
  LQIHLKTMHLDKPEQAHICQYCLEVLPSLYNLNEHLKQVHEAQDPGLIVSAMPAIVYQCN
  FCSEVVNDLNTLQEHIRCSHGFANPAAKDSNAFFCPHCYMGFLTDSSLEEHIRQVHCDLS
  GSRFGSPVLGTPKEPVVEVYSCSYCTNSPIFNSVLKLNKHIKENHKNIPLALNYIHNGKK
  SRALSPLSPVAIEQTSLKMMQAVGGAPARPTGEYICNQCGAKYTSLDSFQTHLKTHLDTV
  LPKLTCPQCNKEFPNQESLLKHVTIHFMITSTYYICESCDKQFTSVDDLQKHLLDMHTFV
  FFRCTLCQEVFDSKVSIQLHLAVKHSNEKKVYRCTSCNWDFRNETDLQLHVKHNHLENQG
  KVHKCIFCGESFGTEVELQCHITTHSKKYNCKFCSKAFHAIILLEKHLREKHCVFETKTP
  NCGTNGASEQVQKEEVELQTLLTNSQESHNSHDGSEEDVDTSEPMYGCDICGAAYTMETL
  LQNHQLRDHNIRPGESAIVKKKAELIKGNYKCNVCSRTFFSENGLREHMQTHLGPVKHYM
  CPICGERFPSLLTLTEHKVTHSKSLDTGNCRICKMPLQSEEEFLEHCQMHPDLRNSLTGF
  RCVVCMQTVTSTLELKIHGTFHMQKTGNGSAVQTTGRGQHVQKLYKCASCLKEFRSKQDL
  VKLDINGLPYGLCAGCVNLSKSASPGINVPPGTNRPGLGQNENLSAIEGKGKVGGLKTRC
  SSCNVKFESESELQNHIQTIHRELVPDSNSTQLKTPQVSPMPRISPSQSDEKKTYQCIKC
  QMVFYNEWDIQVHVANHMIDEGLNHECKLCSQTFDSPAKLQCHLIEHSFEGMGGTFKCPV
  CFTVFVQANKLQQHIFSAHGQEDKIYDCTQCPQKFFFQTELQNHTMTQHSS
• Function: Transcription factor that can both act as an activator or a repressor depending on the context. Involved in BMP signaling and in the regulation of the immature compartment of the hematopoietic system. Associates with SMADs in response to BMP2 leading to activate transcription of BMP target genes. Acts as a transcriptional repressor via its interaction with EBF1, a transcription factor involved specification of B-cell lineage; this interaction preventing EBF1 to bind DNA and activate target genes.
• Tissue Specificity: Predominantly expressed in hematopoietic cells. Present in organs and tissues that contain stem and progenitor cells, myeloid and/or lymphoid: placenta, spleen, lymph nodes, thymus, bone marrow and fetal liver. Within the hematopoietic system, it is abundant in CD34(+) cells but undetectable in mature peripheral blood leukocytes, and its levels rapidly decrease during the differentiation of CD34(+) cells in response to hemopoietins.
• Reactome Pathway:
  Formation of the anterior neural plate (R-HSA-9823739)
  Formation of the posterior neural plate (R-HSA-9832991)
  RUNX2 regulates osteoblast differentiation (R-HSA-8940973)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	Zinc finger protein 521 increases the Hypersensitivity ADR of Phenytoin.	[14]

14 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 Zinc finger protein 521.	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein 521.	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Zinc finger protein 521.	[3]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Zinc finger protein 521.	[4]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Zinc finger protein 521.	[5]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Zinc finger protein 521.	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Zinc finger protein 521.	[7]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Zinc finger protein 521.	[8]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Zinc finger protein 521.	[9]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Zinc finger protein 521.	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Zinc finger protein 521.	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Zinc finger protein 521.	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger protein 521.	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Zinc finger protein 521.	[13]

1 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 Zinc finger protein 521.	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [5] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [9] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [10] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [11] 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.
• [12] 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.
• [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] Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.