Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1Q9TX0)

• DOT Name: Zinc finger MIZ domain-containing protein 1
• Synonyms: PIAS-like protein Zimp10; Retinoic acid-induced protein 17
• Gene Name: ZMIZ1
• Related Disease:
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
  Syndromic intellectual disability
• UniProt ID: ZMIZ1_HUMAN
• PDB ID: 5AIZ
• Pfam ID: PF02891 ; PF18028
• Sequence:
  MNSMDRHIQQTNDRLQCIKQHLQNPANFHNAATELLDWCGDPRAFQRPFEQSLMGCLTVV
  SRVAAQQGFDLDLGYRLLAVCAANRDKFTPKSAALLSSWCEELGRLLLLRHQKSRQSDPP
  GKLPMQPPLSSMSSMKPTLSHSDGSFPYDSVPWQQNTNQPPGSLSVVTTVWGVTNTSQSQ
  VLGNPMANANNPMNPGGNPMASGMTTSNPGLNSPQFAGQQQQFSAKAGPAQPYIQQSMYG
  RPNYPGSGGFGASYPGGPNAPAGMGIPPHTRPPADFTQPAAAAAAAAVAAAAATATATAT
  ATVAALQETQNKDINQYGPMGPTQAYNSQFMNQPGPRGPASMGGSMNPASMAAGMTPSGM
  SGPPMGMNQPRPPGISPFGTHGQRMPQQTYPGPRPQSLPIQNIKRPYPGEPNYGNQQYGP
  NSQFPTQPGQYPAPNPPRPLTSPNYPGQRMPSQPSSGQYPPPTVNMGQYYKPEQFNGQNN
  TFSGSSYSNYSQGNVNRPPRPVPVANYPHSPVPGNPTPPMTPGSSIPPYLSPSQDVKPPF
  PPDIKPNMSALPPPPANHNDELRLTFPVRDGVVLEPFRLEHNLAVSNHVFHLRPTVHQTL
  MWRSDLELQFKCYHHEDRQMNTNWPASVQVSVNATPLTIERGDNKTSHKPLHLKHVCQPG
  RNTIQITVTACCCSHLFVLQLVHRPSVRSVLQGLLKKRLLPAEHCITKIKRNFSSVAASS
  GNTTLNGEDGVEQTAIKVSLKCPITFRRIQLPARGHDCKHVQCFDLESYLQLNCERGTWR
  CPVCNKTALLEGLEVDQYMWGILNAIQHSEFEEVTIDPTCSWRPVPIKSDLHIKDDPDGI
  PSKRFKTMSPSQMIMPNVMEMIAALGPGPSPYPLPPPPGGTNSNDYSSQGNNYQGHGNFD
  FPHGNPGGTSMNDFMHGPPQLSHPPDMPNNMAALEKPLSHPMQETMPHAGSSDQPHPSIQ
  QGLHVPHPSSQSGPPLHHSGAPPPPPSQPPRQPPQAAPSSHPHSDLTFNPSSALEGQAGA
  QGASDMPEPSLDLLPELTNPDELLSYLDPPDLPSNSNDDLLSLFENN
• Function: Acts as a transcriptional coactivator. Increases ligand-dependent transcriptional activity of AR and promotes AR sumoylation. The stimulation of AR activity is dependent upon sumoylation. Also functions as a transcriptional coactivator in the TGF-beta signaling pathway by increasing the activity of the SMAD3/SMAD4 transcriptional complex. Involved in transcriptional activation of a subset of NOTCH1 target genes including MYC. Involved in thymocyte and T cell development. Involved in the regulation of postmitotic positioning of pyramidal neurons in the developing cerebral cortex.
• Tissue Specificity: Expressed most abundantly in ovary and, at lower levels, in prostate, spleen and testis. Weak expression, if any, in thymus, small intestine, colon and peripheral blood leukocytes.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies	DIS1TVDB	Strong	Autosomal dominant	[2]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[3]

23 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 MIZ domain-containing protein 1.	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Zinc finger MIZ domain-containing protein 1.	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Zinc finger MIZ domain-containing protein 1.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc finger MIZ domain-containing protein 1.	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Zinc finger MIZ domain-containing protein 1.	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger MIZ domain-containing protein 1.	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Zinc finger MIZ domain-containing protein 1.	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Zinc finger MIZ domain-containing protein 1.	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Zinc finger MIZ domain-containing protein 1.	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Zinc finger MIZ domain-containing protein 1.	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Zinc finger MIZ domain-containing protein 1.	[15]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Zinc finger MIZ domain-containing protein 1.	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Zinc finger MIZ domain-containing protein 1.	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Zinc finger MIZ domain-containing protein 1.	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Zinc finger MIZ domain-containing protein 1.	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Zinc finger MIZ domain-containing protein 1.	[21]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Zinc finger MIZ domain-containing protein 1.	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger MIZ domain-containing protein 1.	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Zinc finger MIZ domain-containing protein 1.	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Zinc finger MIZ domain-containing protein 1.	[25]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Zinc finger MIZ domain-containing protein 1.	[26]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Zinc finger MIZ domain-containing protein 1.	[27]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Zinc finger MIZ domain-containing protein 1.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Zinc finger MIZ domain-containing protein 1.	[11]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Zinc finger MIZ domain-containing protein 1.	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Zinc finger MIZ domain-containing protein 1.	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Zinc finger MIZ domain-containing protein 1.	[16]

References

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• [2] A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations. Neurogenetics. 2015 Oct;16(4):287-98. doi: 10.1007/s10048-015-0452-2. Epub 2015 Jul 11.
• [3] ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder. Am J Hum Genet. 2019 Feb 7;104(2):319-330. doi: 10.1016/j.ajhg.2018.12.007. Epub 2019 Jan 10.
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• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
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• [17] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [24] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
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• [27] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [28] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.