Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4CYWC1)

• DOT Name: Pogo transposable element with ZNF domain (POGZ)
• Synonyms: Suppressor of hairy wing homolog 5; Zinc finger protein 280E; Zinc finger protein 635
• Gene Name: POGZ
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
  Advanced cancer
  Autism
  Autism spectrum disorder
  Epilepsy
  Intellectual disability
  Kabuki syndrome
  Mowat-Wilson syndrome
  Pervasive developmental disorder
  Movement disorder
  Neurodevelopmental disorder
• UniProt ID: POGZ_HUMAN
• PDB ID: 2E72; 2N3A; 6EMP
• Pfam ID: PF03184 ; PF03221
• Sequence:
  MADTDLFMECEEEELEPWQKISDVIEDSVVEDYNSVDKTTTVSVSQQPVSAPVPIAAHAS
  VAGHLSTSTTVSSSGAQNSDSTKKTLVTLIANNNAGNPLVQQGGQPLILTQNPAPGLGTM
  VTQPVLRPVQVMQNANHVTSSPVASQPIFITTQGFPVRNVRPVQNAMNQVGIVLNVQQGQ
  TVRPITLVPAPGTQFVKPTVGVPQVFSQMTPVRPGSTMPVRPTTNTFTTVIPATLTIRST
  VPQSQSQQTKSTPSTSTTPTATQPTSLGQLAVQSPGQSNQTTNPKLAPSFPSPPAVSIAS
  FVTVKRPGVTGENSNEVAKLVNTLNTIPSLGQSPGPVVVSNNSSAHGSQRTSGPESSMKV
  TSSIPVFDLQDGGRKICPRCNAQFRVTEALRGHMCYCCPEMVEYQKKGKSLDSEPSVPSA
  AKPPSPEKTAPVASTPSSTPIPALSPPTKVPEPNENVGDAVQTKLIMLVDDFYYGRDGGK
  VAQLTNFPKVATSFRCPHCTKRLKNNIRFMNHMKHHVELDQQNGEVDGHTICQHCYRQFS
  TPFQLQCHLENVHSPYESTTKCKICEWAFESEPLFLQHMKDTHKPGEMPYVCQVCQYRSS
  LYSEVDVHFRMIHEDTRHLLCPYCLKVFKNGNAFQQHYMRHQKRNVYHCNKCRLQFLFAK
  DKIEHKLQHHKTFRKPKQLEGLKPGTKVTIRASRGQPRTVPVSSNDTPPSALQEAAPLTS
  SMDPLPVFLYPPVQRSIQKRAVRKMSVMGRQTCLECSFEIPDFPNHFPTYVHCSLCRYST
  CCSRAYANHMINNHVPRKSPKYLALFKNSVSGIKLACTSCTFVTSVGDAMAKHLVFNPSH
  RSSSILPRGLTWIAHSRHGQTRDRVHDRNVKNMYPPPSFPTNKAATVKSAGATPAEPEEL
  LTPLAPALPSPASTATPPPTPTHPQALALPPLATEGAECLNVDDQDEGSPVTQEPELASG
  GGGSGGVGKKEQLSVKKLRVVLFALCCNTEQAAEHFRNPQRRIRRWLRRFQASQGENLEG
  KYLSFEAEEKLAEWVLTQREQQLPVNEETLFQKATKIGRSLEGGFKISYEWAVRFMLRHH
  LTPHARRAVAHTLPKDVAENAGLFIDFVQRQIHNQDLPLSMIVAIDEISLFLDTEVLSSD
  DRKENALQTVGTGEPWCDVVLAILADGTVLPTLVFYRGQMDQPANMPDSILLEAKESGYS
  DDEIMELWSTRVWQKHTACQRSKGMLVMDCHRTHLSEEVLAMLSASSTLPAVVPAGCSSK
  IQPLDVCIKRTVKNFLHKKWKEQAREMADTACDSDVLLQLVLVWLGEVLGVIGDCPELVQ
  RSFLVASVLPGPDGNINSPTRNADMQEELIASLEEQLKLSGEHSESSTPRPRSSPEETIE
  PESLHQLFEGESETESFYGFEEADLDLMEI
• Function: Plays a role in mitotic cell cycle progression and is involved in kinetochore assembly and mitotic sister chromatid cohesion. Probably through its association with CBX5 plays a role in mitotic chromosome segregation by regulating aurora kinase B/AURKB activation and AURKB and CBX5 dissociation from chromosome arms. Promotes the repair of DNA double-strand breaks through the homologous recombination pathway.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[1]
Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome	DISZ0GS1	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Altered Expression	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Kabuki syndrome	DISZN97H	Strong	Altered Expression	[6]
Mowat-Wilson syndrome	DISD1AW7	Strong	Altered Expression	[6]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[7]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[8]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[9]

6 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 Pogo transposable element with ZNF domain (POGZ).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pogo transposable element with ZNF domain (POGZ).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pogo transposable element with ZNF domain (POGZ).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pogo transposable element with ZNF domain (POGZ).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pogo transposable element with ZNF domain (POGZ).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Pogo transposable element with ZNF domain (POGZ).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Pogo transposable element with ZNF domain (POGZ).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Pogo transposable element with ZNF domain (POGZ).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pogo transposable element with ZNF domain (POGZ).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Pogo transposable element with ZNF domain (POGZ).	[15]

References

• [1] POGZ-related epilepsy: Case report and review of the literature. Am J Med Genet A. 2019 Aug;179(8):1631-1636. doi: 10.1002/ajmg.a.61206. Epub 2019 May 28.
• [2] 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.
• [3] A meta-analysis of multiple matched aCGH/expression cancer datasets reveals regulatory relationships and pathway enrichment of potential oncogenes.PLoS One. 2019 Jul 23;14(7):e0213221. doi: 10.1371/journal.pone.0213221. eCollection 2019.
• [4] Rare inherited missense variants of POGZ associate with autism risk and disrupt neuronal development.J Genet Genomics. 2019 May 20;46(5):247-257. doi: 10.1016/j.jgg.2019.04.002. Epub 2019 May 18.
• [5] Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome).Am J Med Genet A. 2020 Jan;182(1):38-52. doi: 10.1002/ajmg.a.61380. Epub 2019 Nov 29.
• [6] Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.Genome Med. 2016 Nov 1;8(1):105. doi: 10.1186/s13073-016-0359-z.
• [7] A novel de novo POGZ mutation in a patient with intellectual disability.J Hum Genet. 2016 Apr;61(4):357-9. doi: 10.1038/jhg.2015.156. Epub 2016 Jan 14.
• [8] Expanding the phenotypic spectrum of truncating POGZ mutations: Association with CNS malformations, skeletal abnormalities, and distinctive facial dysmorphism.Am J Med Genet A. 2017 Jul;173(7):1965-1969. doi: 10.1002/ajmg.a.38255. Epub 2017 May 7.
• [9] Expression Analyses of POGZ, A Responsible Gene for Neurodevelopmental Disorders, during Mouse Brain Development.Dev Neurosci. 2019;41(1-2):139-148. doi: 10.1159/000502128. Epub 2019 Aug 20.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] 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.
• [16] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [17] 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.