Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2A1WLT)

• DOT Name: Zinc finger MYND domain-containing protein 11
• Synonyms: Adenovirus 5 E1A-binding protein; Bone morphogenetic protein receptor-associated molecule 1; Protein BS69
• Gene Name: ZMYND11
• Related Disease:
  Syndromic complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 30
  Intellectual disability, autosomal dominant 40
  Autosomal dominant non-syndromic intellectual disability
• UniProt ID: ZMY11_HUMAN
• PDB ID: 4NS5; 5HDA
• Pfam ID: PF00439 ; PF00855 ; PF21524
• Sequence:
  MARLTKRRQADTKAIQHLWAAIEIIRNQKQIANIDRITKYMSRVHGMHPKETTRQLSLAV
  KDGLIVETLTVGCKGSKAGIEQEGYWLPGDEIDWETENHDWYCFECHLPGEVLICDLCFR
  VYHSKCLSDEFRLRDSSSPWQCPVCRSIKKKNTNKQEMGTYLRFIVSRMKERAIDLNKKG
  KDNKHPMYRRLVHSAVDVPTIQEKVNEGKYRSYEEFKADAQLLLHNTVIFYGADSEQADI
  ARMLYKDTCHELDELQLCKNCFYLSNARPDNWFCYPCIPNHELVWAKMKGFGFWPAKVMQ
  KEDNQVDVRFFGHHHQRAWIPSENIQDITVNIHRLHVKRSMGWKKACDELELHQRFLREG
  RFWKSKNEDRGEEEAESSISSTSNEQLKVTQEPRAKKGRRNQSVEPKKEEPEPETEAVSS
  SQEIPTMPQPIEKVSVSTQTKKLSASSPRMLHRSTQTTNDGVCQSMCHDKYTKIFNDFKD
  RMKSDHKRETERVVREALEKLRSEMEEEKRQAVNKAVANMQGEMDRKCKQVKEKCKEEFV
  EEIKKLATQHKQLISQTKKKQWCYNCEEEAMYHCCWNTSYCSIKCQQEHWHAEHKRTCRR
  KR
• Function: Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at 'Lys-36' (H3.3K36me3) and regulates RNA polymerase II elongation. Does not bind other histone H3 subtypes (H3.1 or H3.2). Colocalizes with highly expressed genes and functions as a transcription corepressor by modulating RNA polymerase II at the elongation stage. Binds non-specifically to dsDNA. Acts as a tumor-suppressor by repressing a transcriptional program essential for tumor cell growth; (Microbial infection) Inhibits Epstein-Barr virus EBNA2-mediated transcriptional activation and host cell proliferation, through direct interaction.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic complex neurodevelopmental disorder	DISJ2RXI	Definitive	Autosomal dominant	[1]
Intellectual disability, autosomal dominant 30	DIS41NFU	Strong	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[3]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[4]

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 MYND domain-containing protein 11.	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Zinc finger MYND domain-containing protein 11.	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Zinc finger MYND domain-containing protein 11.	[11]

8 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 MYND domain-containing protein 11.	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Zinc finger MYND domain-containing protein 11.	[7]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Zinc finger MYND domain-containing protein 11.	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Zinc finger MYND domain-containing protein 11.	[9]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Zinc finger MYND domain-containing protein 11.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Zinc finger MYND domain-containing protein 11.	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger MYND domain-containing protein 11.	[14]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Zinc finger MYND domain-containing protein 11.	[15]

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] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion syndrome, is associated with syndromic intellectual disability. Eur J Med Genet. 2014 Nov-Dec;57(11-12):636-8. doi: 10.1016/j.ejmg.2014.09.002. Epub 2014 Sep 30.
• [4] Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014 Oct;46(10):1063-71. doi: 10.1038/ng.3092. Epub 2014 Sep 14.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] 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.
• [11] 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.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [14] 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.
• [15] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.